Pyrimidyl sulphone amide derivatives as chemokine receptor modulators

ABSTRACT

A compound of formula (I), pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof for the treatment of asthma, allergic rhinitis, COPD, inflammatory bowel disease, irritable bowel syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the national phase application under 35 U.S.C. § 371of PCT International Application No. PCT/GB2003/003175, filed Jul. 23,2003, which claims priority to Great Britain Application Serial No.0217431.6, filed Jul. 27, 2002.

The present invention relates to certain heterocyclic compounds,processes and intermediates used in their preparation, pharmaceuticalcompositions containing them and their use in therapy.

Chemokines play an important role in immune and inflammatory responsesin various diseases and disorders, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis. These small secreted molecules are a growingsuperfamily of 8-14 kDa proteins characterised by a conserved cysteinemotif. At the present time, the chemokine superfamily comprises threegroups exhibiting characteristic structural motifs, the C—X—C, C—C andC—X₃—C families. The C—X—C and C—C families have sequence similarity andare distinguished from one another on the basis of a single amino acidinsertion between the NH-proximal pair of cysteine residues. The C—X₃—Cfamily is distinguished from the other two families on the basis ofhaving a triple amino acid insertion between the NH-proximal pair ofcysteine residues.

The C—X—C chemokines include several potent chemoattractants andactivators of neutrophils such as interleukin-8 (IL-8) andneutrophil-activating peptide 2 (NAP-2).

The C—C chemokines include potent chemoattractants of monocytes andlymphocytes but not neutrophils. Examples include human monocytechemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated onActivation, Normal T Expressed and Secreted), eotaxin and the macrophageinflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

The C—X₃—C chemokine (also known as fractalkine) is a potentchemoattractant and activator of microglia in the central nervous system(CNS) as well as of monocytes, T cells, NK cells and mast cells.

Studies have demonstrated that the actions of the chemokines aremediated by subfamilies of G protein-coupled receptors, among which arethe receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—C family); CXCR1,CXCR2, CXCR3, CXCR4 and CXCR5 (for the C—X—C family) and CX₃CR1 for theC—X₃—C family. These receptors represent good targets for drugdevelopment since agents which modulate these receptors would be usefulin the treatment of disorders and diseases such as those mentionedabove.

The present invention provides compounds of formula (1), apharmaceutically acceptable salt, solvate or in vivo hydrolysable esterthereof:

wherein R¹ is a group selected from C₃₋₇carbocyclyl, C₁₋₈alkyl,C₂₋₆alkenyl and C₂₋₆alkynyl;wherein the group is optionally substituted by 1, 2 or 3 substituentsindependently selected from fluoro, nitrile, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶,—COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, phenyl orheteroaryl; wherein phenyl and heteroaryl are optionally substituted by1, 2 or 3 substituents independently selected from halo, cyano, nitro,—OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶,—NR⁸SO₂R⁹, C₁₋₆alkyl and trifluoromethyl;wherein R² is C₃₋₇carbocyclyl, optionally substituted by 1, 2 or 3substituents independently selected from:

-   (a) fluoro, —OR⁴, —NR⁵R⁶ —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰,    —SO₂NR⁵R⁶, —NR⁸SO₂R⁹;-   (b) a 3-8 membered ring optionally containing 1, 2 or 3 atoms    selected from O, S, —NR⁸ and whereby the ring is optionally    substituted by C₁₋₃alkyl or fluoro; or-   (c) phenyl or heteroaryl, each of which is optionally substituted by    1, 2 or 3 substituents independently selected from halo, cyano,    nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —NR⁸COR⁹, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹,    C₁₋₆alkyl and trifluoromethyl;    or R² is a group selected from C₁₋₈alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl    wherein the group is substituted by 1, 2 or 3 substituents    independently selected from hydroxy, amino, C₁₋₆alkoxy,    C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, N—(C₁₋₆alkyl)-N-(phenyl)amino,    N—C₁₋₆alkylcarbamoyl, N,N-di(C₁₋₆alkyl)carbamoyl,    N—(C₁₋₆alkyl)-N-(phenyl)carbamoyl, carboxy, phenoxycarbonyl,    —NR⁸COR⁹, —SO₂R¹⁰, —SO₂NR⁵R⁶ and —NR⁸SO₂R⁹;    wherein R³ is hydrogen or independently R²;-   R⁴ is hydrogen or a group selected from C₁₋₆alkyl and phenyl,    wherein the group is optionally substituted by 1 or 2 substituents    independently selected from halo, phenyl, —OR¹¹ and —NR¹²R¹³;-   R⁵ and R⁶ are independently hydrogen or a group selected from    C₁₋₆alkyl and phenyl wherein the group is optionally substituted by    1, 2 or 3 substituents independently selected from halo, phenyl,    —OR¹⁴, —NR¹⁵R¹⁶, —COOR¹⁴, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SO₂R¹⁰,    —SONR¹⁵R¹⁶ and NR¹⁵SO₂R¹⁶ or-   R⁵ and R⁶ together with the nitrogen atom to which they are attached    form a 4- to 7-membered saturated heterocyclic ring system    optionally containing a further heteroatom selected from oxygen and    nitrogen atoms, which ring is optionally substituted by 1, 2 or 3    substituents independently selected from phenyl, —OR¹⁴, —COOR¹⁴,    —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SO₂R¹⁰, —SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or    C₁₋₆alkyl (optionally substituted by 1 or 2 substituents    independently selected from halo, —NR¹⁵R¹⁶ and —OR¹⁷ groups);-   R¹⁰ is hydrogen or a group selected from C₁₋₆alkyl or phenyl,    wherein the group is optionally substituted by 1, 2 or 3    substituents independently selected from halo, phenyl, —OR¹⁷ and    —NR¹⁵R¹⁶; and each of R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴ R¹⁵, R¹⁶, R¹⁷    is independently hydrogen, C₁₋₆alkyl or phenyl;-   X is hydrogen, halo, cyano, nitro, hydroxy, C₁₋₆alkoxy (optionally    substituted by 1 or 2 substituents selected from halo, —OR¹¹ and    —NR¹²R¹³), —NR⁵R⁶, —COOR⁷, —NR⁸COR⁹, thio, C₁₋₆alkylthio (optionally    substituted by 1 or 2 substituents selected from halo, —OR¹⁷,    —NR¹⁵R¹⁶), —SO₂R¹⁰ or a group selected from C₃₋₇carbocyclyl,    C₁₋₈alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl, wherein the group is    optionally substituted by 1, 2 or 3 substituents independently    selected from halo, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰,    —SO₂R¹⁰, —SO₂NR⁵R⁶ and —NR⁸SO₂R⁹;-   R^(x) is trifluoromethyl, —NR⁵R⁶, phenyl, napthyl, monocyclic or    bicyclic heteroaryl wherein a heteroring may be partially or fully    saturated and one or more ring carbon atoms may form a carbonyl    group, and wherein each phenyl or heteroaryl group is optionally    substituted by 1, 2 or 3 substituents independently selected from    halo, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COR⁷—COOR⁷, —NR⁸COR⁹,    —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁₋₆alkyl or trifluoromethyl;    or R^(x) is a group selected from C₃₋₇carbocyclyl, C₁₋₈alkyl,    C₂₋₆alkenyl and C₂₋₆alkynyl whereby the group is optionally    substituted by 1, 2 or 3 substituents independently selected from    halo, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COR⁷, —COOR⁷, —NR⁸COR⁹, —SR¹⁰,    —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, phenyl or heteroaryl; and wherein    each phenyl or heteroaryl group is optionally substituted by 1, 2 or    3 substituents independently selected from halo, cyano, nitro, —OR⁴,    —NR⁵R⁶, —CONR⁵R⁶, —COR⁷, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰,    —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁₋₆alkyl or trifluoromethyl;    or R^(x) and X together form a 4 to 8-membered sulfonamide ring    optionally substituted by 1, 2 or 3 substituents independently    selected from halo, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰,    —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, phenyl or heteroaryl; wherein phenyl    and heteroaryl are optionally substituted by 1, 2 or 3 substituents    independently selected from halo, cyano, nitro, —OR⁴, —NR⁵R⁶,    —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹,    C₁₋₆alkyl and trifluoromethyl.

Certain compounds of formula (1) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (1) and mixtures thereof including racemates.

The synthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Similarly, the above-mentioned activity may be evaluatedusing the standard laboratory techniques referred to hereinafter.

Within the present invention it is to be understood that a compound offormula (1) or a salt, solvate or in vivo hydrolysable ester thereof mayexhibit the phenomenon of tautomerism and that the formulae drawingswithin this specification can represent only one of the possibletautomeric forms. It is to be understood that the invention encompassesany tautomeric form and mixtures thereof and is not to be limited merelyto any one tautomeric form utilised within the formulae drawings. Theformulae drawings within this specification can represent only one ofthe possible tautomeric forms and it is to be understood that thespecification encompasses all possible tautomeric forms of the compoundsdrawn not just those forms which it has been possible to showgraphically herein.

It is also to be understood that certain compounds of formula (1) andsalts thereof can exist in solvated as well as unsolvated forms such as,for example, hydrated forms. It is to be understood that the inventionencompasses all such solvated forms.

The present invention relates to the compounds of formula (1) ashereinbefore defined as well as to the salts thereof. Salts for use inpharmaceutical compositions will be pharmaceutically acceptable salts,but other salts may be useful in the production of the compounds offormula (1) and their pharmaceutically acceptable salts.Pharmaceutically acceptable salts of the invention may, for example,include acid addition salts of the compounds of formula (1) ashereinbefore defined which are sufficiently basic to form such salts.Such acid addition salts include for example salts with inorganic ororganic acids affording pharmaceutically acceptable anions such as withhydrogen halides (especially hydrochloric or hydrobromic acid of whichhydrochloric acid is particularly preferred) or with sulphuric orphosphoric acid, or with trifluoroacetic, citric or maleic acid.Suitable salts include hydrochlorides, hydrobromides, phosphates,sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates,acetates, benzoates, citrates, maleates, fumarates, succinates,lactates, tartrates, oxalates, methanesulphonates orp-toluenesulphonates. Pharmaceutically acceptable salts of the inventionmay also include basic addition salts of the compounds of formula (1) ashereinbefore defined which are sufficiently acidic to form such salts.Such salts may be formed with an inorganic or organic base which affordsa pharmaceutically acceptable cation. Such salts with inorganic ororganic bases include for example an alkali metal salt, such as alithium, sodium or potassium salt, an alkaline earth metal salt such asa calcium or magnesium salt, an ammonium salt or an organic amine salt,for example a salt with methylamine, dimethylamine, trimethylamine,triethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.Other basic addition salts include aluminium, zinc, benzathine,chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine,meglumine, tromethamine or procaine.

The present invention further relates to an in vivo hydrolysable esterof a compound of formula (1). An in vivo hydrolysable ester of acompound of formula (1) which contains carboxy or hydroxy group is, forexample a pharmaceutically acceptable ester which is cleaved in thehuman or animal body to produce the parent acid or alcohol. Such esterscan be identified by administering, for example, intravenously to a testanimal, the compound under test and subsequently examining the testanimal's body fluid.

Suitable pharmaceutically acceptable esters for carboxy includeC₁₋₆alkoxymethyl esters for example methoxymethyl, C₁₋₆alkanoyloxymethylesters for example pivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

Suitable pharmaceutically-acceptable esters for hydroxy includeinorganic esters such as phosphate esters (including phosphoramidiccyclic esters) and α-acyloxyalkyl ethers and related compounds which asa result of the in vivo hydrolysis of the ester breakdown to give theparent hydroxy group/s. Examples of α-acyloxyalkyl ethers includeacetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection ofin-vivo hydrolysable ester forming groups for hydroxy includeC₁₋₁₀alkanoyl, for example acetyl; benzoyl; phenylacetyl; substitutedbenzoyl and phenylacetyl, C₁₋₁₀alkoxycarbonyl (to give alkyl carbonateesters), for example ethoxycarbonyl; di-(C₁₋₄)alkylcarbamoyl andN-(di-(C₁₋₄)alkylaminoethyl)-N—(C₁₋₄)alkylcarbamoyl (to givecarbamates); di-(C₁₋₄)alkylaminoacetyl and carboxyacetyl. Examples ofring substituents on phenylacetyl and benzoyl include aminomethyl,(C₁₋₄)alkylaminomethyl and di-((C₁₋₄)alkyl)aminomethyl, and morpholinoor piperazino linked from a ring nitrogen atom via a methylene linkinggroup to the 3- or 4-position of the benzoyl ring. Other interestingin-vivo hyrolysable esters include, for example,R^(A)C(O)O(C₁₋₆)alkyl-CO—, wherein R^(A) is for example,benzyloxy-(C₁₋₄)alkyl, or phenyl). Suitable substituents on a phenylgroup in such esters include, for example,4-(C₁₋₄)piperazino-(C₁₋₄)alkyl, piperazino-(C₁₋₄)alkyl andmorpholino-(C₁₋₄)alkyl.

In this specification the term “alkyl” includes both straight-chain andbranched-chain alkyl groups. However references to individual alkylgroups such as “propyl” are specific for the straight chain version onlyand references to individual branched-chain alkyl groups such as t-butylare specific for the branched chain version only. For example,“C₁₋₃alkyl” includes methyl, ethyl, propyl and isopropyl and examples of“C₁₋₆alkyl” include the examples of “C₁₋₃alkyl”and additionally t-butyl,pentyl, 2,3-dimethylpropyl, 3-methylbutyl and hexyl. Examples of“C₁₋₈alkyl” include the examples of “C₁₋₆alkyl” and additionally heptyl,2,3-dimethylpentyl, 1-propylbutyl and octyl. An analogous conventionapplies to other terms, for example “C₂₋₆alkenyl” includes vinyl, allyl,1-propenyl, 2-butenyl, 3-butenyl, 3-methylbut-1-enyl, 1-pentenyl and4-hexenyl and examples of “C₂₋₆alkynyl” includes ethynyl, 1-propynyl,3-butynyl, 2-pentynyl and 1-methylpent-2-ynyl.

“C₃₋₇carbocyclyl” is a saturated, partially saturated or unsaturated,monocyclic ring containing 3 to 7 carbon ring atoms wherein a —CH₂—group can optionally be replaced by a —C(O)—. Suitable examples of“carbocyclyl” are cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl,cyclohexenyl, 4-oxocyclohex-1-yl and 3-oxocyclohept-5-en-1-yl.

The term “halo” refers to fluoro, chloro, bromo and iodo.

Examples of “C₁₋₆alkoxy” include methoxy, ethoxy, propoxy, isopropoxy,butyloxy, pentyloxy, 1-ethylpropoxy and hexyloxy. Examples of“C₁₋₆alkylamino” include methylamino, ethylamino, propylamino,butylamino and 2-methylpropylmino. Examples of “di(C₁₋₆alkyl)amino”include dimethylamino, N-methyl-N-ethylamino, diethylamino,N-propyl-N-3-methylbutylamino. Examples of“N—(C₁₋₆alkyl)-N-(phenyl)amino” include N-methyl-N-phenylamino,N-propyl-N-phenylamino and N-(2-methylbutyl)-N-phenylamino. Examples of“N—(C₁₋₆alkyl)carbamoyl” are N-methylcarbamoyl, N-ethylcarbamoyl andN-(2-ethylbutylcarbamoyl. Examples of“N—(C₁₋₆alkyl)-N-(phenyl)carbamoyl” include N-methyl-N-phenylcarbamoyl,N-butyl-N-phenylcarbamoyl and N-(3-methylpentyl)-N-(phenyl)carbamoyl.Examples of “N,N-di(C₁₋₆alkyl)carbamoyl” include N,N-dimethylcarbamoyl,N-methyl-N-ethylcarbamoyl and N-propyl-N-(2-methylbutyl)carbamoyl.Examples of “C₁₋₆alkylthio” include methylthio, ethylthio, propylthio,butylthio and 2-methylbutylthio.

“Heteroaryl” is a monocyclic or bicyclic aryl ring containing 5 to 10ring atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen,sulphur or oxygen. Examples of heteroaryl include pyrrolyl, furanyl,thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, benzfuranyl, benzthieno, indolyl,benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl,benzisothiazolyl, benztriazolyl, quinolinyl, isoquinolinyl andnaphthiridinyl. Conveniently heteroaryl is selected from imidazolyl,pyrazolyl, thiazolyl, isoxazolyl, furanyl, thienyl, isoxazolyl, orindazolyl.

Examples of “a 3-8 membered ring optionally containing 1, 2 or 3 atomsselected from O, S and NR⁸” include oxetanyl, azetidinyl, benzodiazolyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl,homopiperidinyl and homopiperazinyl tetrahydrodioxanyl, such asoxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl,homopiperidinyl and homopiperazinyl, further such as pyrrolidinyl,tetrahydropyridinyl, piperidinyl, piperazinyl, and morpholinyl.

Examples of “a 4- to 7-membered saturated heterocyclic ring system”include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,homopiperazinyl and morpholinyl.

Where optional substituents are chosen from “1, 2 or 3” groups it is tobe understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups. An analogous conventionapplies to substituents chosen from “1 or 2” groups.

Preferred values of R¹, R², R³, X and R^(x) are as follows. Such valuesmay be used where appropriate with any of the definitions, claims orembodiments defined hereinbefore or hereinafter.

In one aspect of the present invention there is provided a compound offormula (1) as depicted above wherein R¹ is C₁₋₈alkyl optionallysubstituted by 1, 2 or 3 substituents independently selected fromnitrile, phenyl or heteroaryl, wherein phenyl and heteroaryl areoptionally substituted by 1, 2 or 3 substituents independently selectedfrom halo, cyano, —OR⁴, —SR¹⁰, C₁₋₆alkyl and trifluoromethyl.

In another aspect of the invention R¹ is benzyl optionally substitutedby 1, 2, or 3, such as 1 or 2 substituents independently selected fromfluoro, chloro, bromo, methoxy, methyl and trifluoromethyl. A furtheraspect R¹ is benzyl.

In a further aspect R¹ is monofluorobenzyl such as 2-fluorobenzyl,monochlorobenzyl such as 3-chlorobenzyl, difluorobenzyl such as2,3-difluorobenzyl, fluorochlorobenzyl such as 3-chloro-2-fluorobenzyl,trifluorobenzyl such as 2, 3, 4-trifluorobenzyl.

In one aspect of the invention R² is C₁₋₈alkyl substituted by 1, 2 or 3substituents independently selected from hydroxy, amino, C₁₋₆alkoxy,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, N—(C₁₋₆alkyl)-N-(phenyl)amino,N—C₁₋₆alkylcarbamoyl, N,N-di(C₁₋₆alkyl)carbamoyl,N—(C₁₋₆alkyl)-N-(phenyl)carbamoyl, carboxy, phenoxycarbonyl, —NR⁸COR⁹,—SO₂R¹⁰, —SO₂NR⁵R⁶ and —NR⁸SO₂R⁹.

In another aspect R² is C₁₋₄alkyl substituted by 1 or 2 hydroxy groups,conveniently 1 hydroxy group.

In a further aspect R² is 2-hydroxy-1-methylethyl,1-(hydroxymethyl)propyl, 2-hydroxy-1-(hydroxymethyl)ethyl, or2-hydroxy-1,1-dimethylethyl, especially 2-hydroxy-1-methylethyl

In one aspect of the invention R³ is hydrogen.

In one aspect of the invention R⁴ is hydrogen, C₁₋₄alkyl for examplemethyl, or phenyl.

In one aspect of the invention R⁵ is hydrogen, C₁₋₄alkyl or phenyl.

In one aspect of the invention R⁶ is hydrogen, C₁₋₄alkyl or phenyl.

In one aspect of the invention R¹⁰ is hydrogen, C₁₋₄alkyl or phenyl.

In one aspect of the invention X is hydrogen, halo, cyano, nitro,hydroxy, thio, C₁₋₆alkylthio (optionally substituted by 1 or 2substituents selected from halo, —OR¹⁷, —NR¹⁵R¹⁶), C₁₋₈alkyl (optionallysubstituted by 1, 2 or 3 substituents independently selected from halo,—OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶ and—NR⁸SO₂R⁹).

In another aspect X is hydrogen, halo, cyano, nitro, hydroxy, thio, C₁₋₄alkyl or C₁₋₄ alkoxy (optionally substituted by 1, 2 or 3 substituentsindependently selected from halo, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷,—NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶ and —NR⁸SO₂R⁹), C₁₋₄ alkylthio orC₁₋₄ alkylamino (optionally substituted by 1 or 2 substituents selectedfrom halo, —OR¹⁷, —NR¹⁵R¹⁶),

In another aspect X is hydrogen, halo or C₁₋₄ alkyl (optionallysubstituted by 1, 2 or 3 substituents independently selected from halo,—OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶ and—NR⁸SO₂R⁹),

In another aspect X is hydrogen.

In one aspect of the invention R^(x) is trifluoromethyl, —NR⁵R⁶, phenyl,napthyl, monocyclic or bicyclic heteroaryl wherein a heteroring may bepartially or fully saturated and one or more ring carbon atoms may forma carbonyl group, and wherein each phenyl or heteroaryl group isoptionally substituted by 1, 2 or 3 substituents independently selectedfrom halo, cyano, nitro, —OR⁴, —NR⁵R⁵, —CONR⁵R⁶, —COR⁷, —COOR⁷,—NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁₋₆alkyl ortrifluoromethyl;

or R^(x) is a group selected from C₃₋₇carbocyclyl, C₁₋₈alkyl,C₂₋₆alkenyl and C₂₋₆alkynyl whereby the group is optionally substitutedby 1, 2 or 3 substituents independently selected from halo, —OR⁴,—NR⁵R⁶, —CONR⁵R⁶, —COR⁷, —COOR⁷, —N⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶,—NR⁸SO₂R⁹, phenyl or heteroaryl; and wherein each phenyl or heteroarylgroup is optionally substituted by 1, 2 or 3 substituents independentlyselected from halo, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COR⁷—COOR⁷,—NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R, —NR⁸SO₂R⁹, C₁₋₆alkyl ortrifluoromethyl;

In a further aspect of the invention R^(x) is phenyl, heteroaryl, —NR⁵R⁶or a group selected from C₁₋₈alkyl whereby the group is optionallysubstituted by 1, 2 or 3 substituents independently selected from halo,—OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶,—NR⁸SO₂R⁹, phenyl or heteroaryl; and wherein each phenyl or heteroarylgroup is optionally substituted by 1, 2 or 3 substituents independentlyselected from halo, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷,—NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁₋₆alkyl ortrifluoromethyl.

In a further aspect R^(x) is methyl, phenyl, 1-methylimidazolyl,1,2-dimethylimidazolyl, or isoxazolyl.

In a further aspect R^(x) is methyl, phenyl or 1-methylimidazolyl or1,2-dimethylimidazolyl.

In a further aspect R^(x) is —NR⁵R⁶ such as azetidinyl, pyrolidinyl,piperazinyl or morpholinyl.

A preferred class of compound is of formula (1) wherein;

-   R¹ is C₁₋₈alkyl optionally substituted by 1, 2 or 3 substituents    independently selected from nitrile, phenyl or heteroaryl, wherein    phenyl and heteroaryl are optionally substituted by 1, 2 or 3    substituents independently selected from halo, cyano, —OR⁴, —SR¹⁰,    C₁₋₆alkyl and trifluoromethyl;-   R² is C₁₋₈alkyl substituted by 1, 2 or 3 substituents independently    selected from hydroxy, amino, C₁₋₆alkoxy, C₁₋₆alkylamino,    di(C₁₋₆alkyl)amino, N—(C₁₋₆alkyl)-N-(phenyl)amino,    N—C₁₋₆alkylcarbamoyl, N,N-di(C₁₋₆alkyl)carbamoyl,    N—(C₁₋₆alkyl)-N-(phenyl)carbamoyl, carboxy, phenoxycarbonyl,    —NR⁸COR⁹, —SO₂R¹⁰, —SO₂NR⁵R⁶ and —NR⁸SO₂R⁹;-   R³ is hydrogen;-   R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ R¹⁵, R¹⁶ and R¹⁷ are    independently hydrogen, C₁₋₄alkyl or phenyl; and-   X is hydrogen, halo, cyano, nitro, hydroxy, thio, C₁₋₆alkylthio    (optionally substituted by 1 or 2 substituents selected from halo,    —OR¹⁷, —NR¹⁵R¹⁶), C₁₋₈alkyl (optionally substituted by 1, 2 or 3    substituents independently selected from halo, —OR⁴, —NR⁵R⁶,    —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶ and    —NR⁸SO₂R⁹);-   R^(x) is —NR⁵R⁶, phenyl, napthyl, monocyclic or bicyclic heteroaryl    wherein a heteroring may be partially or fully saturated and one or    more ring carbon atoms may form a carbonyl group, and wherein each    phenyl or heteroaryl group is optionally substituted by 1, 2 or 3    substituents independently selected from halo, cyano, nitro, —OR⁴,    —NR⁵R⁶, —CONR⁵R⁶, —COR⁷—COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶,    —NR⁸SO₂R⁹, C₁₋₆alkyl or trifluoromethyl;    or R^(x) is C₁₋₈alkyl optionally substituted by 1, 2 or 3    substituents independently selected from halo, —OR⁴, —NR⁵R⁶,    —CONR⁵R⁶, —COR⁷, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶,    —NR⁸SO₂R⁹, phenyl or heteroaryl; and wherein each phenyl or    heteroaryl group is optionally substituted by 1, 2 or 3 substituents    independently selected from halo, cyano, nitro, —OR⁴, —NR⁵R⁶,    —CONR⁵R⁶, —COR⁷, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶,    —NR⁸SO₂R⁹, C₁₋₆alkyl or trifluoromethyl;

Another preferred class of compound is of formula (1) wherein;

-   R¹ is benzyl optionally substituted by 1, 2 or 3, such as 2,    substituents independently selected from fluoro, chloro, bromo,    methoxy, methyl and trifluoromethyl;-   R² is C₁₋₄alkyl substituted by 1 or 2 hydroxy groups;-   R³ is hydrogen;-   X is hydrogen; and-   R^(x) is methyl, phenyl, 1-methylimidazolyl, 1,2-dimethylimidazolyl,    isoxazolyl or N,N-dimethylamino. Alternatively R^(x) is —NR⁵R⁶—such    as azetidinyl, pyrolidinyl piperazinyl, piperidinyl or morpholinyl

In another class R¹ is benzyl optionally substituted by3-chloro-2-fluoro, 2,3-difluoro or 2,3,4-trifluoro

-   R² is 2-hydroxy-1-methylethyl-   R³ is hydrogen-   X is hydrogen-   R^(x) is azetidinyl, pyrolidinyl or morpholinyl, N,N-dimethylamino,    piperidinyl, methyl, 1-methylimidazolyl and 1,2-dimethylimidazolyl.

Convenient compounds of the invention include each exemplified compound,each selected independently and pharmaceutically acceptable salts, invivo hydrolysable esters thereof.

Particular compounds of the invention include:

-   N-(2-[(3-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)methanesulfonamide-   N-[2-[(3-Chloro-2-fluorobenzyl)thio]-6-[(2-hydroxy-1-methylethyl)amino]-4-pyrimidinyl]-4-morpholinesulfonamide-   N-[2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-6-[(2-hydroxy-1-methylethyl)amino]-4-pyrimidinyl]-1,2-dimethyl-1H-imidazole-4-sulfonamide-   N-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)piperidine-1-sulfonamide-   N-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)pyrrolidine-1-sulfonamide-   N-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)azetidine-1-sulfonamide-   N-{6-{[(1R)-2-Hydroxy-1-methylethyl]amino}-2-[(2,3,4-trifluorobenzyl)thio]-pyrimidin-4-yl}morpholine-4-sulfonamide-   N-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)morpholine-4-sulfonamide-   N-(2-[(3-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)azetidine-1-sulfonamide-   N-{6-{[(1R)-2-Hydroxy-1-methylethyl]amino}-2-[(2,3,4-trifluorobenzyl)thio]-pyrimidin-4-yl}azetidine-1-sulfonamide-   N′-(2-[(3-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)-N,N-dimethylsulfamide,    and-   N-[2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-6-[(R)-(2-hydroxy-1-methylethyl)amino]-4-pyrimidinyl]-1-methyl-1H-imidazole-4-sulfonamide    and pharmaceutically acceptable salts, solvates or in vivo    hydrolysable esters thereof. Each of the above mentioned compound    and the pharmaceutically acceptable salt, solvate or int vivo    hydrolysable ester thereof, individually is a preferred aspect of    the invention.

Further particular compounds of the invention include:

-   N-(2-[(2,3-difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)methanesulfonamide;-   N-(2-[(2,3-difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-1-methyl-1H-imidazole-4-sulfonamide;-   N-(2-(benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-methanesulfonamide;    and-   N-(2-(benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)benzenesulfonamide;    and pharmaceutically acceptable salts, solvates or in vivo    hydrolysable esters thereof. Each of the above mentioned compound    and the pharmaceutically acceptable salt, solvate or in vivo    hydrolysable ester thereof, individually is a preferred aspect of    the invention.

The present invention farther provides processes for the preparation ofcompounds of formula (1) as defined above which comprise:

Process 1

(a) Treating a Compound of Formula (2):

wherein R¹, R² and R³ are as defined in formula (1) and X is hydrogenwith sulfonyl chlorides (R^(x)SO₂Cl) where R^(x) is as defined informula (1).and optionally thereafter (i), (ii), (iii), (iv), or (v) in any order:

-   i) removing any protecting groups;-   ii) converting the compound of formula (1) into a further compound    of formula (1)-   iii) forming a salt-   iv) forming a prodrug-   v) forming an in vivo hydrolysable ester.

Reaction of compounds of formula (2) wherein R¹, R² and R³ are asdefined in formula (1) and X is hydrogen with sulfonyl chlorides(R^(x)SO₂Cl) can be carried out in the presence of a suitable base andsolvent. Examples of suitable bases include trialkylamines, such astriethylamine or N,N-diisopropylethylamine or pyridine (optionally inthe presence of a catalyst such as 4-dimethylaminopyridine). Suitablesolvents include dichloromethane, pyridine, N,N-dimethylamides,1-methyl-2-pyrolidone, and ethers such as tetrahydrofuran, 1,4-dioxane,glyme and diglyme. Preferably N,N-dimethylformamide is used. Thetemperature of the reaction can be performed between −10° C. and 100° C.Preferably N,N-diisopropylethylamine in dichloromethane or pyridine with4-dimethylaminopyridine both at ambient temperature are used.

Compounds of formula (2) wherein R¹, R² and R³ and X are as defined informula (1), can be prepared from compounds of formula (3) wherein R¹and X are as defined in formula (1) and L is halogen by treatment withnucleophilic amines NR²R³ as defined in formula (1) in the presence of asuitable base and solvent.

Examples of suitable bases include trialkylamines, such as triethylamineor N,N-diisopropylethylamine. Suitable solvents includeN,N-dimethylamides, 1-methyl-2-pyrolidone, and ethers such astetrahydrofuran, 1,4-dioxane, glyme and diglyme. The temperature of thereaction can be performed between 0° C. and 150° C. PreferablyN,N-diisopropylethylamine in 1-methyl-2-pyrolidinone at 120° C. is used.

Compounds of formula (3) wherein R¹ and X are as defined in formula (1)and L is halogen may be prepared by treating a compound of formula (3)wherein R¹ and X are as defined in formula (1) and L is OH with ahalogenating agent such as phosphorous oxychloride. The reaction may becarried out in the presence of an N,N-dialkylaniline, such asN,N-dimethylaniline at reflux.

Compounds of formula (3) wherein R¹ and X are as defined in formula (1)and L is OH;

may be prepared from compounds of formula (4) wherein X is as defined informula (1) by reaction with alkylhalides (R₁A) where R₁ is as definedin formula (1) and A is halogen in the presence of a suitable base andsolvent.

Examples of suitable bases include the alkali metal hydroxides such asLi, Na, or K, or metal carbonates such as Li, Na, K or Cs, or metalacetates such as Li, Na, K or Cs, or metal alkoxides such as Li, Na,K-tert-butoxide. Suitable solvents include N,N-dimethylamides,1-methyl-2-pyrolidinone, ethers such as tetrahydrofuran, 1,4-dioxane,glyme and diglyme and alcohols such as methanol, ethanol andtert-butanol. Preferably potassium hydroxide in N,N-dimethylformamide atambient temperature is used.

Compounds of formula (3) wherein R¹ and X are as defined in formula (1)and L is halogen;

may also be prepared from compounds of formula (5) wherein X and R¹ areas defined in formula (1) and L is halogen by reaction with concentratedammonium hydroxide solution in the presence of a suitable solvent.Suitable solvents include N-methyl-2-pyrolidone, acetonitrile and etherssuch as tetrahydrofuran, 1,4-dioxane, glyme and diglyme. The temperatureof the reaction can be performed between 0° C. and 150° C. Preferablyacetonitrile at 60° C. is used.

Compounds of formula (5) wherein R¹ and X are as defined in formula (1)and L is halogen may be prepared from compounds of formula (5) whereinR¹ and X are as defined in formula (1) and L is OH by reaction with ahalogenating agent such as phosphorous oxychloride. The reaction may becarried out in the presence of N,N-dimethylaniline at reflux.

Compounds of formula (5) wherein R¹ and X are as defined in formula (1)and L is OH;

may be prepared from compounds of formula (6) wherein X are as definedin formula (1) and L is OH by reaction with alkylhalides (R₁A) where R₁is as defined in formula (1) and A is halogen in the presence of asuitable base and solvent.

Examples of suitable bases include the alkali metal hydroxides such asLi, Na, or K, or metal carbonates such as Li, Na, K or Cs, or metalacetates such as Li, Na, K or Cs, or metal alkoxides such as Li, Na, Ktert-butoxide. Suitable solvents include N,N-dimethylamides,1-methyl-2-pyrolidone, ethers such as tetrahydrofuran, 1,4-dioxane,glyme and diglyme and alcohols such as methanol, ethanol andtert-butanol. Preferably potassium hydroxide in N,N-dimethylformamide atambient temperature is used.

Compounds of formulae (4) and (6) are either commercially available, arewell known in the literature or may be easily prepared using knowntechniques.

Process 2

(b) Treating a Compound of Formula (7):

wherein R¹, R^(x) and X are as defined in formula (1), L is a halogenand Y is either hydrogen or a protecting group with nucleophilic aminesof the type NR²R³ as defined in formula (1) in the presence or absenceof a suitable base and solvent.and optionally thereafter (i), (ii), (iii), (iv) or (v) in any order:

-   i) removing any protecting groups;-   ii) converting the compound of formula (1) into a further compound    of formula (1)-   iii) forming a salt-   iv) forming a prodrug-   v) forming an in vivo hydrolysable ester.

Examples of suitable bases include trialkylamines, such as triethylamineor N,N-diisopropylethylamine. Suitable solvents includeN,N-dimethylamides, 1-methyl-2-pyrolidone, and ethers such astetrahydrofuran, 1,4-dioxane, glyme and diglyme. The temperature of thereaction can be performed between 0° C. and 150° C. Preferably1-methyl-2-pyrolidinone at 80° C. is used.

Compounds of formula (7) wherein R¹, R^(x) and X are as defined informula (1) and L is halogen and Y is a protecting group or hydrogen;

may be prepared from compounds of formula (5) wherein X and R¹ are asdefined in formula (1) and L is a halogen by reaction with sulfonamidesor sulfamides of formula R^(x)SO₂NH₂ where R^(x) is as defined informula (1) in the presence of a suitable base and solvent.

Examples of suitable bases include the alkali metal hydrides such as Naor K. Suitable solvents include N,N-dimethylamides,1-methyl-2-pyrolidinone, ethers such as tetrahydrofuran, 1,4-dioxane,glyme and diglyme. The temperature of the reaction may be performedbetween 0° C. and 100° C. Preferably sodium hydride inN,N-dimethylformamide at ambient temperature is employed.

Compounds of formula (5) can be prepared as described in process (1).

Compounds of formula R^(x)SO₂NH₂ where Rx is NR⁵R⁶ may be prepared fromsulfamide in the presence of a suitable solvent. Suitable solventsinclude N,N-dimethylamides, 1-methyl-2-pyrolidinone, dichloromethane,chloroform, ethers such as tetrahydrofuran, 1,4-dioxane, glyme anddiglyme and alcohols such as methanol, ethanol and tert-butanol.Preferably 1,4-dioxane is used at 110° C.

Process 3

(c) Treating a Compound of Formula (8):

wherein R¹, R², R³, R^(x) and X are as defined in formula (1) and L ishalogen, with sulfonamides of formula R^(x)SO₂NH₂ where R^(x) is asdefined in formula (1) except NR⁵R⁶ in the presence of a suitable baseand solvent.and optionally thereafter (i), (ii), (iii), (iv) or (v) in any order:

-   i) removing any protecting groups;-   ii) converting the compound of formula (1) into a further compound    of formula (1)-   iii) forming a salt-   iv) forming a prodrug-   v) forming an in vivo hydrolysable ester.

Examples of suitable bases include the alkali metal hydrides such as Naor K, or metal alkoxides such as Li, Na or K-tert-butoxide, or metalcarbonates such as Na, K, Cs. Suitable solvents includeN,N-dimethylamides, 1-methyl-2-pyrolidinone, ethers such astetrahydrofuran, 1,4-dioxane, glyme and diglyme. Preferably sodiumhydride in N,N-dimethylformamide at ambient temperature is employed.

Compounds of formula (8) wherein R¹, R², R³ and X are as defined informula (1) and L is halogen;

may be prepared from compounds of formula (5) wherein X and R¹ are asdefined in formula (1) and L is a halogen by reaction with nucleophilicamines NR²R³ as defined in formula (1) in the presence a suitable baseand solvent. Examples of suitable bases include trialkylamines, such astriethylanine or N,N-diisopropylethylamine. Suitable solvents includeN,N-dimethylamides, 1-methyl-2-pyrolidone, and ethers such astetrahydrofuran, 1,4-dioxane, glyme and diglyme. The temperature of thereaction can be performed between 0° C. and 150° C. PreferablyN,N-diisopropylethylamine in N-methylpyrolidinone is used at roomtemperature.

Compounds of formula (5) can be prepared as described in process (1).

Compounds of formula R^(x)SO₂NH₂ where R^(x) is as defined in formula(1), except NR⁵R⁶, are either commercially available or well known inthe literature or may be prepared from the corresponding commerciallyavailable or well known in the literature sulfonyl chlorides R^(x)SO₂Cl.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups in the starting reagents or intermediate compounds may needto be protected by protecting groups. Thus, the preparation of thecompounds of formula (1) may involve, at an appropriate stage, theremoval of one or more protecting groups. The protection anddeprotection of functional groups is fully described in ‘ProtectiveGroups in Organic Chemistry’, edited by J. W. F. McOmie, Plenum Press(1973), and ‘Protective Groups in Organic Synthesis’, 2nd edition, T. W.Greene & P. G. M. Wuts, Wiley-Interscience (1991).

Compounds of formulae (2), (3), (4) and (5), (6), (7), and (8) areeither commercially available, are well known in the literature or maybe easily prepared using known techniques.

A compound of formula (1) may be prepared from another compound offormula (1) by chemical modification. Examples of chemical modificationsinclude standard alkylation, arylation, heteroarylation, acylation,sulphonylation, phosphorylation, aromatic halogenation and couplingreactions. These reactions may be used to add new substituents or tomodify existing substituents. Alternatively, existing substituents incompounds of formula (1) may be modified by, for example, oxidation,reduction, elimination, hydrolysis or other cleavage reactions to yieldother compounds of formula (1).

Novel intermediate compounds form a further aspect of the invention.

The compounds of formula (1) above may be converted to apharmaceutically acceptable salt, solvate or in vivo hydrolysable esterthereof, as discussed above. The salt is preferably a basic additionsalt.

The compounds of formula (1) have activity as pharmaceuticals, inparticular as modulators of chemokine receptor (especially CXCR2)activity, and may be used in the treatment (therapeutic or prophylactic)of conditions/diseases in human and non-human animals which areexacerbated or caused by excessive or unregulated production ofchemokines. Examples of such conditions/diseases include (each takenindependently):

-   -   (1) (the respiratory tract) obstructive airways diseases        including chronic obstructive pulmonary disease (COPD); asthma,        such as bronchial, allergic, intrinsic, extrinsic and dust        asthma, particularly chronic or inveterate asthma (e.g. late        asthma and airways hyper-responsiveness); bronchitis; acute,        allergic, atrophic rhinitis and chronic rhinitis including        rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta,        rhinitis sicca and rhinitis medicamentosa; membranous rhinitis        including croupous, fibrinous and pseudomembranous rhinitis and        scrofoulous rhinitis; seasonal rhinitis including rhinitis        nervosa (hay fever) and vasomotor rhinitis; sarcoidosis,        farmer's lung and related diseases, fibroid lung and idiopathic        interstitial pneumonia;    -   (2) (bone and joints) rheumatoid arthritis, seronegative        spondyloarthropathies (including ankylosing spondylitis,        psoriatic arthritis and Reiter's disease), Behchet's disease,        Sjogren's syndrome and systemic sclerosis;    -   (3) (skin) psoriasis, atopical dermatitis, contact dermatitis        and other eczmatous dermitides, seborrhoetic dermatitis, Lichen        planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa,        urticaria, angiodermas, vasculitides, erythemas, cutaneous        eosinophilias, uveitis, Alopecia greata and vernal        conjunctivitis;    -   (4) (gastrointestinal tract) Coeliac disease, proctitis,        eosinopilic gastro-enteritis, mastocytosis, Crohn's disease,        ulcerative colitis, indeterminate colitis, microscopic colitis,        inflammatory bowel disease, irritable bowel syndrome,        non-inflammatory diarrhea, food-related allergies which have        effects remote from the gut, e.g., migraine, rhinitis and        eczema;    -   (5) (central and peripheral nervous system) Neurodegenerative        diseases and dementia disorders, e.g. Alzheimer's disease,        amyotrophic lateral sclerosis and other motor neuron diseases,        Creutzfeldt-Jacob's disease and other prion diseases, HIV        encephalopathy (AIDS dementia complex), Huntington's disease,        frontotemporal dementia, Lewy body dementia and vascular        dementia; polyneuropathies, e.g. Guillain-Barre syndrome,        chronic inflammatory demyelinating polyradiculoneuropathy,        multifocal motor neuropathy, plexopathies; CNS demyelination,        e.g. multiple sclerosis, acute disseminated/haemorrhagic        encephalomyelitis, and subacute sclerosing panencephalitis;        neuromuscular disorders, e.g. myasthenia gravis and        Lambert-Eaton syndrome; spinal diorders, e.g. tropical spastic        paraparesis, and stiff-man syndrome: paraneoplastic syndromes,        e.g. cerebellar degeneration and encephalomyelitis; CNS trauma;        migraine; and stroke.    -   (6) (other tissues and systemic disease) atherosclerosis,        Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus,        systemic lupus, erythematosus, Hashimoto's thyroiditis, type I        diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE        syndrome, lepromatous leprosy, and idiopathic thrombocytopenia        pupura; post-operative adhesions, and sepsis.    -   (7) (allograft rejection) acute and chronic following, for        example, transplantation of kidney, heart, liver, lung, bone        marrow, skin and cornea; and chronic graft versus host disease;    -   (8) Cancers, especially non-small cell lung cancer (NSCLC),        malignant melanoma, prostate cancer and squamous sarcoma, and        tumour metastasis, non melanoma skin cancer and chemoprevention        metastases;    -   (9) Diseases in which angiogenesis is associated with raised        CXCR2 chemokine levels (e.g. NSCLC, diabetic retinopathy);    -   (10) Cystic fibrosis;    -   (11) Burn wounds & chronic skin ulcers;    -   (12) Reproductive Diseases (e.g. Disorders of ovulation,        menstruation and implantation, Pre-term labour, Endometriosis);    -   (13) Re-perfusion injury in the heart, brain, peripheral limbs        and other organs, inhibition of atherosclerosis.

Thus, the present invention provides a compound of formula (1), or apharmaceutically-acceptable salt, solvate or an in vivo hydrolysableester thereof, as hereinbefore defined for use in therapy.

Preferably the compounds of the invention are used to treat diseases inwhich the chemokine receptor belongs to the CXC chemokine receptorsubfamily, more preferably the target chemokine receptor is the CXCR2receptor.

Particular conditions which can be treated with the compounds of theinvention are cancer, diseases in which angiogenesis is associated withraised CXCR2 chemokine levels, and inflammatory diseases such as asthma,allergic rhinitis, COPD, rheumatoid arthritis, psoriasis, inflammatorybowel diseases, osteoarthritis or osteoporosis.

As a further aspect of the present invention, certain compounds offormula (1) may have utility as antagonists of the CX3CR1 receptor. Suchcompounds are expected to be particularly useful in the treatment ofdisorders within the central and peripheral nervous system and otherconditions characterized by an activation of microglia and/orinfiltration of leukocytes (e.g. stroke/ischemia and head trauma).

In a further aspect, the present invention provides a compound offormula (1), or a pharmaceutically acceptable salt, solvate or in vivohydrolysable ester thereof, as hereinbefore defined for use as amedicament.

In a still further aspect, the present invention provides the use of acompound of formula (1), or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof, as hereinbefore defined for useas a medicament for the treatment of human diseases or conditions inwhich modulation of chemokine receptor activity is beneficial.

In a still further aspect, the present invention provides the use of acompound of formula (1), or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof, as hereinbefore defined for useas a medicament for the treatment of asthma, allergic rhinitis, cancer,COPD, rheumatoid arthritis, psoriasis, inflammatory bowel diseases,osteoarthritis or osteoporosis.

In a further aspect, the present invention provides the use of acompound of formula (1), or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof, as hereinbefore defined in themanufacture of a medicament for use in therapy.

In a still further aspect, the present invention provides the use of acompound of formula (1), or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof, as hereinbefore defined in themanufacture of a medicament for the treatment of human diseases orconditions in which modulation of chemokine receptor activity isbeneficial.

In a still further aspect, the present invention provides the use of acompound of formula (1), or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof, as hereinbefore defined in themanufacture of a medicament for the treatment of asthma, allergicrhinitis, cancer, COPD, rheumatoid arthritis, psoriasis, inflammatorybowel diseases, osteoarthritis or osteoporosis.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention still further provides a method of treating a chemokinemediated disease wherein the chemokine binds to a chemokine (especiallyCXCR2) receptor, which comprises administering to a patient atherapeutically effective amount of a compound of formula, or apharmaceutically acceptable salt, solvate or in vivo hydrolysable ester,as hereinbefore defined.

The invention also provides a method of treating an inflammatorydisease, especially asthma, allergic rhinitis, COPD, rheumatoidarthritis, psoriasis, inflammatory bowel diseases, osteoarthritis orosteoporosis, in a patient suffering from, or at risk of, said disease,which comprises administering to the patient a therapeutically effectiveamount of a compound of formula (1), or a pharmaceutically acceptablesalt, solvate or in vivo hydrolysable ester thereof, as hereinbeforedefined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated.

The compounds of formula (1) and pharmaceutically acceptable salts,solvates or in vivo hydrolysable esters thereof may be used on their ownbut will generally be administered in the form of a pharmaceuticalcomposition in which formula (1) compound/salt/solvate/ester (activeingredient) is in association with a pharmaceutically acceptableadjuvant, diluent or carrier. Depending on the mode of administration,the pharmaceutical composition will preferably comprise from 0.05 to 99%w (percent by weight), more preferably from 0.05 to 80% w, still morepreferably from 0.10 to 70% w, and even more preferably from 0.10 to 50%w, of active ingredient, all percentages by weight being based on totalcomposition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (1), or a pharmaceutically acceptablesalt, solvate or in vivo hydrolysable ester thereof, as hereinbeforedefined, in association with a pharmaceutically acceptable adjuvant,diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (1), or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof, as hereinbefore defined, with apharmaceutically acceptable adjuvant, diluent or carrier. Thepharmaceutical compositions may be administered topically (e.g. to thelung and/or airways or to the skin) in the form of solutions,suspensions, heptafluoroalkane aerosols and dry powder formulations; orsystemically, e.g. by oral administration in the form of tablets,capsules, syrups, powders or granules, or by parenteral administrationin the form of solutions or suspensions, or by subcutaneousadministration or by rectal administration in the form of suppositoriesor transdermally. Preferably the compounds of the invention areadministered orally.

In addition to their use as therapeutic medicines, the compounds offormula (1) and their pharmaceutically acceptable salts, solvate or invivo hydrolysable esters are also useful as pharmacological tools in thedevelopment and standardisation of in vitro and in vivo test systems forthe evaluation of the effect of chemokine modulation activity inlabatory animals such as cats, dogs, rabbits, monkeys, rats and mice, aspart of the search for new therapeutic agents.

The invention further relates to combination therapies wherein acompound of formula (1) or a pharmaceutically acceptable salts, solvateor in vivo hydrolysable ester thereof, or a pharmaceutical compositionor formulation comprising a compound of formula (1) is administeredconcurrently or sequentially with therapy and/or an agent for thetreatment of any one of asthma, allergic rhinitis, cancer, COPD,rheumatoid arthritis, psoriasis, inflammatory bowel disease, irritablebowel syndrome, osteoarthritis or osteoporosis.

In particular, for the treatment of the inflammatory diseases rheumatoidarthritis, psoriasis, inflammatory bowel disease, irritable bowelsyndrome, COPD, asthma and allergic rhinitis the compounds of theinvention may be combined with agents such as TNF-α inhibitors such asanti-TNF monoclonal antibodies (such as Remicade, CDP-870 andD.sub2.E.sub7.) and TNF receptor immunoglobulin molecules (such asEnbrel.reg.), non-selective COX-1/COX-2 inhibitors (such as piroxicam,diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin), COX-2 inhibitors (such as meloxicam,celecoxib, rofecoxib, valdecoxib and etoricoxib) low dose methotrexate,lefunomide; ciclesonide; hydroxychloroquine, d-penicillamine, auranofinor parenteral or oral gold. For inflammatory bowel disease and irritablebowel disorder further convenient agents include sulphasalazine and5-ASAs, topical and systemic steroids, immunomodulators andimmunosuppressants, antibiotics, probiotics and anti-integrins.

The present invention still further relates to the combination of acompound of the invention together with a leukotriene biosynthesisinhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activatingprotein (FLAP) antagonist such as zileuton; ABT-761; fenleuton;tepoxalin; Abbott-79175; Abbott-85761;N-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di-tert-butylphenolhydrazones; methoxytetrahydropyrans such as Zeneca ZD-2138; the compoundSB-210661; pyridinyl-substituted 2-cyanonaphthalene compounds such asL-739,010; 2-cyanoquinoline compounds such as L-746,530; indole andquinotine compounds such as MK-591, MK-886, and BAY x 1005.

The present invention still further relates to the combination of acompound of the invention together with a receptor antagonist forleukotrienes LTB.sub4., LTC.sub4., LTD.sub4., and LTE.sub4. selectedfrom the group consisting of the phenothiazin-3-ones such as L-651,392;amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast;benzenecarboximidamides such as BIIL 284/260; and compounds such aszafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679),RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.

The present invention still further relates to the combination of acompound of the invention together with a PDE4 inhibitor includinginhibitors of the isoform PDE4D.

The present invention still further relates to the combination of acompound of the invention together with a antihistaminic H.sub1.receptor antagonists such as cetirizine, loratadine, desloratadine,fexofenadine, astemizole, azelastine, and chlorpheniramine.

The present invention still further relates to the combination of acompound of the invention together with a gastroprotective H.sub2.receptor antagonist.

The present invention still further relates to the combination of acompound of the invention together with an α.sub1.- andα.sub2.-adrenoceptor agonist vasoconstrictor sympathomimetic agent, suchas propylhexedrine, phenylephrine, phenylpropanolamine, seudoephedrine,naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozolinehydrochloride, xylometazoline hydrochloride, and ethylnorepinephrinehydrochloride.

The present invention still further relates to the combination of acompound of the invention together with anticholinergic agents such asipratropium bromide; tiotropium bromide; oxitropium bromide;pirenzepine; and telenzepine.

The present invention still further relates to the combination of acompound of the invention together with a β.sub1.- toβ.sub4.-adrenoceptor agonists such as metaproterenol, isoproterenol,isoprenaline, albuterol, salbutamol, formoterol, salmeterol,terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol; ormethylxanthanines including theophylline and aminophylline; sodiumcromoglycate; or muscarinic receptor (M1, M2, and M3) antagonist.

The present invention still further relates to the combination of acompound of the invention together with an insulin-like growth factortype I (IGF-1) mimetic.

The present invention still further relates to the combination of acompound of the invention together with an inhaled glucocorticoid withreduced systemic side effects, such as prednisone, prednisolone,flunisolide, triamcinolone acetonide, beclomethasone dipropionate,budesonide, fluticasone propionate, and mometasone furoate.

The present invention still further relates to the combination of acompound of the invention together with an inhibitor of matrixmetalloproteases (MMPs), i.e., the stromelysins, the collagenases, andthe gelatinases, as well as aggrecanase; especially collagenase-1(MMP-1), collagenase-2 (M-8), collagenase-3 (MMP-13), stromelysin-1(MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-12.

The present invention still further relates to the combination of acompound of the invention together with other modulators of chemokinereceptor function such as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—C family); CXCR1,CXCR3, CXCR4 and CXCR5 (for the C—X—C family) and CX₃CR1 for the C—X₃—Cfamily.

The present invention still further relates to the combination of acompound of the invention together with antiviral agents such asViracept, AZT, aciclovir and famciclovir, and antisepsis compounds suchas Valant.

The present invention still further relates to the combination of acompound of the invention together with cardiovascular agents such ascalcium channel blockers, lipid lowering agents such as statins,fibrates, beta-blockers, Ace inhibitors, Angiotensin-2 receptorantagonists and platelet aggregation inhibitors.

The present invention still further relates to the combination of acompound of the invention together with CNS agents such asantidepressants (such as sertraline), anti-Parkinsonian drugs (such asdeprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine andrasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopaminereuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamineagonists and inhibitors of neuronal nitric oxide synthase), andanti-Alzheimer's drugs such as donepezil, tacrine, COX-2 inhibitors,propentofylline or metryfonate.

The present invention still further relates to the combination of acompound of the invention together with (i) tryptase inhibitors; (ii)platelet activating factor (PAF) antagonists; (iii) interleukinconverting enzyme (ICE) inhibitors; (iv) IMPDH inhibitors; (v) adhesionmolecule inhibitors including VLA-4 antagonists; (vi) cathepsins; (vii)MAP kinase inhibitors; (viii) glucose-6 phosphate dehydrogenaseinhibitors; (ix) kinin-B.sub1.- and B.sub2.-receptor antagonists; (x)anti-gout agents, e.g., colchicine; (xi) xanthine oxidase inhibitors,e.g., allopurinol; (xii) uricosuric agents, e.g., probenecid,sulfinpyrazone, and benzbromarone; (xiii) growth hormone secretagogues;(xiv) transforming growth factor (TGFβ); (xv) platelet-derived growthfactor (PDGF); (xvi) fibroblast growth factor, e.g., basic fibroblastgrowth factor (bFGF); (xvii) granulocyte macrophage colony stimulatingfactor (GM-CSF); (xviii) capsaicin cream; (xix) Tachykinin NK.sub1. andNK.sub3. receptor antagonists selected from the group consisting ofNKP-608C; SB-233412 (talnetant); and D-4418; (xx) elastase inhibitorsselected from the group consisting of UT-77 and ZD-0892; (xxi) TNFδconverting enzyme inhibitors (TACE); (xxii) induced nitric oxidesynthase inhibitors (iNOS) or (xxiii) chemoattractantreceptor-homologous molecule expressed on TH2 cells, (CRTH2antagonists).

The compounds of the present invention may also be used in combinationwith osteoporosis agents such as roloxifene, droloxifene, lasofoxifeneor fosomax and immunosuppressant agents such as FK-506, rapamycin,cyclosporine, azathioprine, and methotrexate.

The compounds of the invention may also be used in combination withexisting therapeutic agents for the treatment of osteoarthritis.Suitable agents to be used in combination include standard non-steroidalanti-inflammatory agents (hereinafter NSAID's) such as piroxicam,diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin, COX-2 inhibitors such as celecoxib,valdecoxib, rofecoxib and etoricoxib, analgesics and intraarticulartherapies such as corticosteroids and hyaluronic acids such as hyalganand synvisc and P2X7 receptor antagonists.

The compounds of the invention can also be used in combination withexisting therapeutic agents for the treatment of cancer. Suitable agentsto be used in combination include:

-   (i) antiproliferative/antineoplastic drugs and combinations thereof,    as used in medical oncology, such as alkylating agents (for example    cis-platin, carboplatin, cyclophosphamide, nitrogen mustard,    melphalan, chlorambucil, busulphan and nitrosoureas);    antimetabolites (for example antifolates such as fluoropyrimidines    like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine    arabinoside, hydroxyurea, gemcitabine and paclitaxel (Taxol®);    antitumour antibiotics (for example anthracyclines like adriamycin,    bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin,    mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for    example vinca alkaloids like vincristine, vinblastine, vindesine and    vinorelbine and taxoids like taxol and taxotere); and topoisomerase    inhibitors (for example epipodophyllotoxins like etoposide and    teniposide, amsacrine, topotecan and camptothecin);-   (ii) cytostatic agents such as antioestrogens (for example    tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene),    oestrogen receptor down regulators (for example fulvestrant),    antiandrogens (for example bicalutamide, flutamide, nilutamide and    cyproterone acetate), LHRH antagonists or LHRH agonists (for example    goserelin, leuprorelin and buserelin), progestogens (for example    megestrol acetate), aromatase inhibitors (for example as    anastrozole, letrozole, vorazole and exemestane) and inhibitors of    5α-reductase such as finasteride;-   (iii) Agents which inhibit cancer cell invasion (for example    metalloproteinase inhibitors like marimastat and inhibitors of    urokinase plasminogen activator receptor function);-   (iv) inhibitors of growth factor function, for example such    inhibitors include growth factor antibodies, growth factor receptor    antibodies (for example the anti-erbb2 antibody trastuzumab    [Herceptin™] and the anti-erbb1 antibody cetuximab [C225]), farnesyl    transferase inhibitors, tyrosine kinase inhibitors and    serine/threonine kinase inhibitors, for example inhibitors of the    epidermal growth factor family (for example EGFR family tyrosine    kinase inhibitors such as    N-(3-chlorofluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine    (gefitinib, AZD1839),    N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine    (erlotinib, OSI-774) and    6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine    (CI 1033)), for example inhibitors of the platelet-derived growth    factor family and for example inhibitors of the hepatocyte growth    factor family;-   (v) antiangiogenic agents such as those which inhibit the effects of    vascular endothelial growth factor, (for example the anti-vascular    endothelial cell growth factor antibody bevacizumab [Avastin™],    compounds such as those disclosed in International Patent    Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354)    and compounds that work by other mechanisms (for example linomide,    inhibitors of integrin αvβ3 function and angiostatin);-   (vi) vascular damaging agents such as Combretastatin A4 and    compounds disclosed in International Patent Applications WO    99/02166, WO00/40529, WO 00/41669, WO01/92224, WO02/04434 and    WO02/08213;-   (vii) antisense therapies, for example those which are directed to    the targets listed above, such as ISIS 2503, an anti-ras antisense;-   (viii) gene therapy approaches, including for example approaches to    replace aberrant genes such as aberrant p53 or aberrant BRCA1 or    BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such    as those using cytosine deaminase, thymidine kinase or a bacterial    nitroreductase enzyme and approaches to increase patient tolerance    to chemotherapy or radiotherapy such as multi-drug resistance gene    therapy; and-   (ix) immunotherapy approaches, including for example ex-vivo and    in-vivo approaches to increase the immunogenicity of patient tumour    cells, such as transfection with cytokines such as interleukin 2,    interleukin 4 or granulocyte-macrophage colony stimulating factor,    approaches to decrease T-cell anergy, approaches using transfected    immune cells such as cytokine-transfected dendritic cells,    approaches using cytokine-transfected tumour cell lines and    approaches using anti-idiotypic antibodies.    Pharmacological Data    Ligand Binding Assay

[¹²⁵I]IL-8 (human, recombinant) was purchased from Amersham, U.K. with aspecific activity of 2,000 Ci/mmol. All other chemicals were ofanalytical grade. High levels of hrCXCR2 were expressed in HEK 293 cells(human embryo kidney 293 cells ECACC No. 85120602) (Lee et al. (1992) J.Biol Chem. 267 pp 16283-16291). hrCXCR2 cDNA was amplified and clonedfrom human neutrophil mRNA. The DNA was cloned into PCRScript(Stratagene) and clones were identified using DNA. The coding sequencewas sub-cloned into the eukaryotic expression vector RcCMV (Invitrogen).Plasmid DNA was prepared using Quiagen Megaprep 2500 and transfectedinto HEK 293 cells using Lipofectamine reagent (Gibco BRL). Cells of thehighest expressing clone were harvested in phosphate-buffered salinecontaining 0.2% (w/v) ethylenediaminetetraacetic acid (EDTA) andcentrifuged (200 g, 5 min.). The cell pellet was resuspended in ice coldhomogenisation buffer [10 mM HEPES (pH 7.4), 1 mM dithiothreitol, 1 mMEDTA and a panel of protease inhibitors (1 mM phenyl methyl sulphonylfluoride, 2 μg/ml soybean trypsin inhibitor, 3 mM benzamidine, 0.5 μg/mlleupeptin and 100 μg/ml bacitracin)] and the cells left to swell for 10minutes. The cell preparation was disrupted using a hand held glassmortar/PTFE pestle homogeniser and cell membranes harvested bycentrifugation (45 minutes, 100,000 g, 4° C.). The membrane preparationwas stored at −70° C. in homogenisation buffer supplemented withTyrode's salt solution (137 mM NaCl, 2.7 mM KCl, 0.4 mM NaH₂PO₄), 0.1%(w/v) gelatin and 10% (v/v) glycerol.

All assays were performed in a 96-well MultiScreen 0.45 μm filtrationplates (Millipore, U.K.). Each assay contained ˜50 pM [¹²⁵I]IL-8 andmembranes (equivalent to ˜200,000 cells) in assay buffer [Tyrode's saltsolution supplemented with 10 mM HEPES (pH 7.4), 1.8 mM CaCl₂, 1 mMMgCl₂, 0.125 mg/ml bacitracin and 0.1% (w/v) gelatin]. In addition, acompound of formula (I) according to the Examples was pre-dissolved inDMSO and added to reach a final concentration of 1% (v/v) DMSO. Theassay was initiated with the addition of membranes and after 1.5 hoursat room temperature the membranes were harvested by filtration using aMillipore MultiScreen vacuum manifold and washed twice with assay buffer(without bacitracin). The backing plate was removed from the MultiScreenplate assembly, the filters dried at room temperature, punched out andthen counted on a Cobra □-counter.

The compounds of formula (1) according to the Examples 1-138 were foundto have pIC₅₀ values of greater than (>) 5.0. For example, Examples 3, 4and 116 were found to have pIC₅₀ values of 7.10, 7.10 and 6.80respectively.

Intracellular Calcium Mobilisation Assay

Human neutrophils were prepared from EDTA-treated peripheral blood, aspreviously described (Baly et al. (1997) Methods in Enzymology 287 pp70-72), in storage buffer [Tyrode's salt solution (137 mM NaCl, 2.7 mMKCl, 0.4 mM NaH₂PO₄) supplemented with 5.7 mM glucose and 10 mM HEPES(pH 7.4)].

The chemokine GROδ (human, recombinant) was purchased from R&D Systems(Abingdon, U.K.). All other chemicals were of analytical grade. Changesin intracellular free calcium were measured fluorometrically by loadingneutrophils with the calcium sensitive fluorescent dye, fluo-3, asdescribed previously (Merritt et al. (1990) Biochem. J. 269, pp513-519). Cells were loaded for 1 hour at 37° C. in loading buffer(storage buffer with 0.1% (w/v) gelatin) containing 5 μM fluo-3 AMester, washed with loading buffer and then resuspended in Tyrode's saltsolution supplemented with 5.7 mM glucose, 0.1% (w/v) bovine serumalbumin (BSA), 1.8 mM CaCl₂ and 1 mM MgCl₂. The cells were pipetted intoblack walled, clear bottom, 96 well micro plates (Costar, Boston,U.S.A.) and centrifuged (200 g, 5 minutes, room temperature).

A compound of formula (I) according to the Examples was pre-dissolved inDMSO and added to a final concentration of 0.1% (v/v) DMSO. Assays wereinitiated by the addition of an A₅₀ concentration of GROδ and thetransient increase in fluo-3 fluorescence (δ_(Ex)=490 nm and δ_(Em)=520nm) monitored using a FLIPR (Fluorometric Imaging Plate Reader,Molecular Devices, Sunnyvale, U.S.A.).

The compounds of formula (1) according to the Examples were tested andfound to be antagonists of the CXCR2 receptor in human neutrophils.

The invention will now be illustrated by the following non-limitingExamples in which, unless stated otherwise:

-   -   (i) when given Nuclear Magnetic Resonance (NMR) spectra were        measured on a Varian Unity Inova 300 or 400 MHz spectrometer. ¹H        NMR data is quoted in the form of delta values for major        diagnostic protons, given in parts per million (ppm) relative to        tetramethylsilane (TMS) as an internal standard.    -   (ii) Mass Spectrometry (MS) spectra were measured on a Finnigan        Mat SSQ7000 or Micromass Platform spectrometer.    -   (iii) the title and sub-titled compounds of the Examples and        methods were named using the ACD/Name program (version 4.55)        from Advanced Chemical Development Inc, Canada.    -   (iv) Normal phase column chromatography and normal phase HPLC        was conducted using a silica column. Reverse phase High Pressure        Liquid Chromatography (HPLC) purification was performed using        either a Waters Micromass LCZ with a Waters 600 pump controller,        Waters 2487 detector and Gilson FC024 fraction collector or a        Waters Delta Prep 4000 or a Gilson Auto Purification System,        using a Symmetry, NovaPak or Ex-Terra reverse phase silica        column.    -   (v) The following abbreviations are used:

AcOH acetic acid CHCl₃ chloroform DCM dichloromethane DMFN,N-dimethylformamide DMSO dimethylsulfoxide Et₂O diethyl ether EtOAcethyl acetate MgSO₄ magnesium sulfate NMP 1-methylpyrrolidin-2-one THFtetrahydrofuran H₂O water

EXAMPLE 1N-(2-[(2,3-difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)methanesulfonamide

Methanesulfonyl chloride (0.16 ml) was added to a solution of thesubtitle product of step iv) (0.40 g) and N,N-diisosopropylethylamine(0.5 ml) in DCM (15 ml) and stirring maintained for 2 h. The reactionsolution was extracted with H₂O (2×20 ml) and the organics combined,dried (MgSO₄) and concentrated to yield a brown oil. The residue wasdiluted in THF (10 ml) and treated with 1M tetrabutylammonium fluoridein THF (2 ml) for 30 min at room temperature. The volatiles were removedin vacuo and the residue partitioned between EtOAc (30 ml) and saturatedammonium chloride solution (30 ml). The aqueous layer was furtherextracted with EtOAc (2×20 ml), the organics combined, dried (MgSO₄) andconcentrated to yield a white solid. This material was further purifiedby silica gel chromatography and then reverse phase HPLC(acetonitrile/0.02M ammonium hydroxide (90% to 5% aqueous phase) toyield the title compound as a white solid. Yield: 25 mg.

MS APCI(+ve) 405 [M+H]⁺

¹H NMR δ_((DMSO)) 7.41-7.12 (3H, m), 5.79 (1H, s), 4.70 (1H, br. s),4.38 (2H, s), 3.41-3.25 (2H, m), 3.22 (3H, s), 1.05 (3H, d).

The intermediates for this compound were prepared as follows:

i) 6-Amino-2-[(2,3-difluorobenzyl)thio]pyrimidin-4(3B)-one

An aqueous solution of potassium hydroxide (4.61 g) in H₂O (25 ml) wasadded to a suspension of 4-amino-6-hydroxy-2-mercaptopyrimidinemonohydrate (11.26 g) in DMF (50 ml). Stirring was maintained for 30 minduring which time a solution was obtained, before the dropwise additionof a solution of 2,3-difluorobenzyl bromide (14.46 g) in THF (10 ml).After stirring for 20 h the slurry was diluted with H₂O (500 ml) andstirred for 30 min before filtering. The filtrate was washed with H₂O(4×100 ml) and iso-hexane (4×100 ml) before drying in vacuo for 24 h toafford the subtitle compound as a white solid. Yield: 14.1 g.

MS APCI(+ve) 309 [M+CH₃COO⁻]⁺

ii) 6-Chloro-2-[(2,3-difluorobenzyl)thio]pyrimidin-4-amine

N,N-Dimethylaniline (5 ml) was added to a solution of the subtitleproduct of step i) in phosphorus oxychloride (50 ml) and heated atreflux for 2 h. The reaction was allowed to cool before pouring into hotH₂O (500 ml) and stirring the mixture for 2 h. This mixture wasextracted with DCM (3×250 ml) and the organics combined, dried (MgSO₄)and concentrated in vacuo to afford the subtitle compound as a greenfoam. This crude product was used directly in step iii). Yield: 12.3 g.

MS: APCI(+ve) 329 [M+CH₃COO⁻]⁺

iii)(2R)-2-({6-Amino-2-[(2,3-difluorobenzyl)thio]pyrimidin-4-yl}amino)propan-1-ol

N,N-Diisopropylethylarine (1.92 ml) was added to a solution ofR-alaninol (2.0 ml) and the subtitle product of step ii) (1.9 g) in NMP(10 ml) and stirred at 100° C. for five days before pouring into H₂O(200 ml) and filtration of the precipitate. This solid was dried invacuo to afford the subtitle compound as a yellow solid. Yield: 1.80 g.

MS: APCI(+ve) 327 [M+H]⁺

iv)N-((1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-[(2,3-difluorobenzyl)-thio]pyrimidine-4,6-diamine

Imidazole (1.2 g) was added to a solution of tert-butyldimethylsilylchloride (2.83 g) and the subtitle product of step iii) (1.8 g) in DMF(10 ml). The reaction was stirred for 20 h before partitioning betweenEtOAc (100 ml) and H₂O (200 ml). The aqueous was extracted further withEtOAc (2×100 ml), the organics combined, washed with H₂O (100 ml), brine(100 ml), dried (MgSO₄) and concentrated in vacuo to a crude solid. Thismaterial was purified by column chromatography (50% Et₂O/iso-hexane) toafford the subtitle compound as a yellow oil. Yield: 1.80 g.

MS: APCI(+ve) 441 [M+H]⁺

EXAMPLE 2N-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-1-methyl-1H-imidazole-4-sulfonamide

1-Methyl-1H-imidazole-4-sulfonyl chloride was added to a solution of thesubtitle product of Example 1 step iv) (0.40 g) and4-dimethylaminopyridine (0.12 g) in pyridine (10 ml) at room temperatureand stirred for 20 h. The reaction mixture was partitioned between DCM(50 ml) and copper (II) sulfate solution (60 ml). The aqueous wasextracted further with DCM, the organics combined, dried (MgSO₄) andconcentrated in vacuo. The resulting oil was diluted in THF (10 ml) andtreated with tetrabutylammonium fluoride (1M in THF, 2 ml) for 30 min atroom temperature. The volatiles were removed in vacuo and the residuepartitioned between EtOAc (20 ml) and saturated ammonium chloridesolution (20 ml). The aqueous was further extracted with EtOAc (2×20ml), the organics combined, dried (MgSO₄) and concentrated to yield acrude white solid. This material was further purified by reverse phaseHPLC (acetonitrile/0.02M ammonium hydroxide (90% to 5% aqueous phase))to yield the title compound as a white solid. Yield: 60 mg.

MS APCI(+ve) 471 [M+H]⁺

¹H NMR δ_((DMSO)) 7.83 (m, 1H), 7.75 (s, 1H), 7.33 (m, 3H), 7.11 (m,2H), 5.92 (s, 1H), 4.69 (s, 1H), 4.32 (s, 2H), 3.96 (s, 1H), 3.66 (s,3H), 3.40-3.20 (m, 2H), 1.03 (d, 3H)

EXAMPLE 3N-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-methanesulfonamide

A solution of the subtitle product of step iii) (0.18 g) in THF (10 ml)was treated with tetrabutylammonium fluoride (1M in THF, 2 ml) for 2 hat room temperature. The volatiles were removed in vacuo and the residuepartitioned between EtOAc (20 ml) and saturated ammonium chloridesolution (20 ml). The aqueous was further extracted with EtOAc (2×20ml), the organics combined, dried (MgSO₄) and concentrated to yield acrude white solid. This material was further purified by reverse phaseHPLC (acetonitrile/0.02M ammonium hydroxide (90% to 5% aqueous phase))to yield the title compound as a white solid. Yield: 25 mg.

MS APCI(+ve) 369 [M+H]⁺

¹H NMR δ_((DMSO)) 7.41 (d, 2H), 7.30 (t, 2H), 7.23 (t, 2H), 5.78 (s,1H), 4.71 (t, 1H), 4.32 (s, 2H), 3.40 (dt, 1H), 3.29 (m, 1H), 3.18 (s,3H), 1.07 (d, 3H).

The intermediates for this compound were prepared as follows:

i) (2R)-2-{[6-Amino-2-(benzylthio)pyrimidin-4-yl]amino}propan-1-ol

N,N-Diisopropylethylamine (6.0 ml) was added to a solution of R-alaninol(12.0 ml) and 2-(benzylthio)-6-chloropyrimidin-4-amine (1.9 g) (Nugent,R. A., et al. PCT Int. Appl. 1996. 252 pp. WO9635678-A1) in NMP (6 ml)and stirred at 100° C. for three days before pouring into H₂O (200 ml)and filtration of the precipitate. This solid was dried in vacuo toafford the subtitle compound as a pale sandy yellow solid. Yield: 4.1 g.

MS: APCI(+ve) 291 [M+H]⁺

ii)2-(Benzylthio)-N-((1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)pyrimidine-4,6-diamine

Imidazole (0.29 g) was added to a solution of tert-butyldimethylsilylchloride (0.34 g) and the subtitle product of step i) (0.6 g) in DMF (10ml). The reaction was stirred for 24 h before addition of a furtherequivalent of tert-butyldimethylsilyl chloride and imidazole. Afterstirring for an additional 24 h the reaction mixture was partitionedbetween EtOAc (100 ml) and H₂O (200 ml). The aqueous was extractedfurther with EtOAc (3×100 ml), the organics combined, washed with H₂O(100 ml), brine (100 ml), dried (MgSO₄) and concentrated to a crudesolid. This material was purified by column chromatography (1:1Et₂O/iso-hexane) to afford the subtitle compound as a yellow oil. Yield:0.50 g.

MS: APCI(+ve) 405 [M+H]⁺

iii)N-{2-(Benzylthio)-6-[((1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)amino]-pyrimidin-4-yl}methanesulfonamide

Methanesulfonyl chloride (85 μl) was added to a solution of the subtitleproduct of step ii) (0.20 g) and N,N-diiosopropylethylamine (0.26 ml) inDCM (10 ml) at 0° C. The ice-bath was removed and stirring maintainedfor 2 h. The reaction solution was extracted with H₂O (2×20 ml) and theorganics dried (MgSO₄) and concentrated to yield a brown oil. Theresidue was diluted in methanol (110 ml) and treated with potassiumcarbonate (0.15 g) for 2 h at room temperature. The volatiles wereremoved in vacuo and the residue partitioned between EtOAc (20 ml) andH₂O (20 ml). The aqueous was further extracted with EtOAc (2×20 ml), theorganics combined, dried (MgSO₄) and concentrated to yield the subtitlecompound as a crude white solid. This material was used directly in thenext step. Yield: 0.23 g.

MS APCI(+ve) 483 [M+H]⁺

EXAMPLE 4N-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)benzenesulfonamide

Phenylsulfonyl chloride (0.20 g) was added to a solution of the subtitleproduct of Example 3 step ii) (0.40 g) and 4-dimethylamino pyridine(0.17 g) in pyridine (10 ml) was stirred for 24 h at room temperature.The reaction was quenched with 10% potassium carbonate solution (10 ml)and the aqueous extracted with EtOAc (2×20 ml). The crude material wasdissolved in THF (10 ml) and treated with tetrabutylammonium fluoride(1M in THF, 5 ml) for 15 min at room temperature. The reaction wasquenched with 1M hydrochloric acid (10 ml) and the aqueous extractedwith EtOAc (2×20 ml). The organics were then combined, washed with brine(50 ml), dried (MgSO₄) and concentrated to yield a crude gum which waspurified by column chromatography (2% methanol/DCM) to afford a gum.This material was treated with ethanol (25 ml) and H₂O (5 ml) and thevolatiles removed under reduced pressure to yield the title compound asa white solid. Yield: 0.39 g.

MS APCI(+ve) 431 [M+H]⁺

¹H NMR δ_((DMSO)) 7.87 (d, 2H), 7.60 (m, 3H), 7.35 (d, 2H), 7.28 (t,2H), 7.22 (m, 1H), 5.89 (s, 1H), 4.70 (s, 1H), 4.21 (s, 2H), 4.01 (s,1H), 3.40-3.21 (m, 2H), 1.04 (d, 3H).

EXAMPLE 5N-(2-(Benzylthio)-6-{[(1R)-1-methylpropyl]amino}pyrimidin-4-yl)-3,5-dimethylisoxazole-4-sulfonamide

3,5-Dimethylisoxazole-4-sulfonyl chloride (0.60 g) was added to asolution of the subtitle product of Example 3 step ii) (50 mg) inpyridine (0.5 ml) and N,N-dimethylamino-pyridine (16 mg). The reactionmixture was stirred overnight. To this reaction was added excess aqueoushydrochloric acid (1M) and stirred for 1 h. The solvent was evaporatedand the residue diluted in EtOAc (100 ml). This was washed with H₂O(2×20 ml) and brine (10 ml). The organic layer was dried (MgSO₄) andconcentrated to yield a white solid. This material was purified byreverse phase HPLC (gradient 90% to 5% 0.02M ammoniumhydroxide/acetonitrile) to yield the title compound as a solid. Yield:24 mg.

MS APCI(+ve) 450 [M+H]⁺

¹H NMR δ_((DMSO)) 7.26-7.30 (5H, m), 5.73 (1H, s),5.30 (1H, bs), 4.30(2H, s), 4.0 (1H, br. s), 3.66 (1H, m), 3.54-3.59 (1H, m), 2.65 (3H, s),2.39 (3H, s), 1.21 (3H, d).

EXAMPLE 6N-(2-(Benzylthio)-6-{[(1R)-1-methylpropyl]amino}pyrimidin-4-yl)-1-phenylmethanesulfonamide

Phenylmethanesulfonyl chloride (0.28 g) was added to a solution of thesubtitle product of Example 3 step ii) (0.1 g) in pyridine (1 ml) andN,N-dimethylaminopyridine (30 mg). The reaction mixture was stirred for6 h. To the reaction mixture was added tetrabutylammonium fluoride (7ml, 1M in THF) and stirred for 16 h. The solvent was evaporated and theresidue diluted in EtOAc (100 ml) and hydrochloric acid (1M). This waswashed with H₂O (2×20 ml) and brine (10 ml). The organics were dried(MgSO₄) and concentrated to yield a solid. This material was purified byreverse phase HPLC (90% to 5% 0.02M ammonium hydroxide/acetonitrile) toyield the title compound as a solid. Yield: 30 mg.

MS APCI(+ve) 445 [M+H]⁺

¹H NMR δ_((CDCl3)) 7.24-7.40 (10H, m), 5.76 (1H, s), 5.02 (1H, bs), 4.43(2H, s), 4.31 (2H, s) 4.02 (1H, br. s), 3.65-3.70 (1H, m), 3.51-3.56(1H, m), 1.21 (3H, d)

EXAMPLE 7N-(2-(Benzylthio)-6-{[(1R)-1-methylpropyl]amino}pyrimidin-4-yl)-2-chlorobenzenesulfonamide

The title compound was synthesised according to the procedure of Example6 using 2-chlorobenzenesulfonyl chloride (0.31 g), the subtitle productof Example 3 step ii) (0.1 g), N,N-dimethylaminopyridine (30 mg) andtetrabutylammonium fluoride (4 ml, 1M in THF) to yield the titlecompound as a white solid. Yield: 30 mg.

MS APCI(+ve) 465 [M+H]⁺

¹H NMR δ_((CDCl3)) 8.14 (1H, d), 7.48 (2H, bs),7.22-7.35 (6H, m), 5.84(1H, s), 5.03 (1H, bs), 4.25 (2H, s), 3.98 (1H, bs) 3.54-3.66 (1H, m),3.49-3.54 (1H, m),1.21 (3H, d).

EXAMPLE 8N-(2-(Benzylthio)-6-{[(1R)-1-methylpropyl]amino}pyrimidin-4-yl)-4-cyanobenzenesulfonamide

The title compound was synthesised according to the procedure of Example6 using 4-cyanobenzenesulfonyl chloride (0.30 g), the subtitle productof Example 3 step ii) (0.1 g), N,N-dimethylaminopyridine (30 mg) andtetrabutylammonium fluoride (4 ml, 1M in THF) to yield the titlecompound as a white solid. Yield: 45 mg.

MS APCI(+ve) 456 [M+H]⁺

¹H NMR δ_((CDCl3)) 8.05 (2H, d), 7.74 (2H, d),7.19-7.34 (5H, m), 5.85(1H, s), 5.44 (1H, d), 4.13 (2H, s), 4.00 (1H, bs), 3.68-3.73 (1H, m),3.54-3.59 (1H, m),1.21 (3H, d).

EXAMPLE 9N-(2-(Benzylthio)-6-{[(1R)-1-methylpropyl]amino}pyrimidin-4-yl)-4-chlorobenzenesulfonamide

The title compound was synthesised according to the procedure of Example6 using 4-chlorobenzenesulfonyl chloride (0.31 g), the subtitle productof Example 3 step ii) (0.1 g), N,N-dimethylaminopyridine (30 mg) andtetrabutylammonium fluoride (4 ml, 1M in THF) to yield the titlecompound as a white solid. Yield: 18 mg.

MS APCI(+ve) 465 [M+H]⁺

¹H NMR δ_((CDCl3)) 7.80 (2H, d),7.40 (2H, d), 7.20-7.40 (5H, m), 5.90(1H, s), 5.15 (1H, bs), 4.20 (2H, s), 4.00 (1H, bs) 3.60-3.80 (1H, m),3.42-3.60 (1H, m), 1.21 (3H, d).

EXAMPLE 10N-(2-(Benzylthio)-6-{[(1R)-1-methylpropyl]amino}pyrimidin-4-yl)-2-cyanobenzenesulfonamide

2-Cyanobenzenesulfonyl chloride (0.30 g) was added to the solution ofthe subtitle product of Example 3 step ii) (0.1 g) in pyridine (1 ml)and N,N-dimethylaminopyridine (30 mg). The reaction mixture was stirredfor 4 h. To the reaction mixture was added tetrabutylammonium fluoride(4 ml, 1M in THF) and stirred for 16 h. To this reaction was addedaqueous hydrochloric acid (1M, 30 ml). The solvent was evaporated andthe residue diluted in EtOAc (100 ml). This was washed with H₂O (3×20ml) and brine (10 ml). The organic layer was dried (MgSO₄) andconcentrated to yield a solid. The residue was purified by columnchromatography (EtOAc/iso-hexane 7:3) followed by column chromatography(EtOAc) to yield the title compound. Yield: 30 mg.

MS APCI(+ve) 456 [M+H]⁺

¹H NMR δ_((CDCl3)) 8.20 (1H, d), 7.58-7.62 (1H, m), 7.62-7.78 (1H, m),7.78-8.00 (1H, m), 7.19-7.35 (5H, m), 5.80 (1H, s), 5.48 (1H, bs),4.25(2H, s), 3.50-3.80 (2H, m), 1.21 (3H, d).

EXAMPLE 11N-(2-(Benzylthio)-6-{[(1R)-1-methylpropyl]amino}pyrimidin-4-yl)-3-cyanobenzenesulfonamide

3-Cyanobenzenesulfonyl chloride (0.30 g) was added to the solution ofthe subtitle product of Example 3 step ii) (0.1 g) in pyridine (1 ml)and N,N-dimethylaminopyridine (30 mg). The reaction mixture was stirredfor 4 h. To the reaction mixture was added tetrabutylammonium fluoride(4 ml, 1M in THF) and stirred for 16 h. To this reaction was addedaqueous hydrochloric acid (1M, 30 ml). The solvent was evaporated andthe residue diluted in EtOAc (100 ml). This was washed with H₂O (3×20ml) and brine (10 ml). The organic layer was dried (MgSO₄) andconcentrated to yield a solid. The residue was purified by columnchromatography (EtOAc/iso-hexane 7:3 to 1:1) to yield the title compoundas a white solid. Yield: 45 mg.

MS APCI(+ve) 456 [M+H]⁺

¹H NMR δ_((CDCl3)) 8.20 (1H, s), 8.15 (1H, d), 7.80 (1H, d), 7.60 (1H,t), 7.20-7.40 (6H, m), 5.90 (1H, s), 5.50 (1H, d), 4.32 (2H, s),3.50-3.80 (2H, m), 1.21 (3H, d).

EXAMPLE 12N-(2-(Benzylthio)-6-{[(1R)-1-methylpropyl]amino}pyrimidin-4-yl)-3-chlorobenzenesulfonamide

3-Chlorobenzenesulfonyl chloride (0.30 g) was added to the solution ofthe subtitle product of Example 3 step ii) (0.1 g) in pyridine (1 ml)and N,N-dimethylaminopyridine (30 mg). The reaction mixture was stirredfor 4 h. To the reaction mixture was added tetrabutylammonium fluoride(4 ml, 1M in THF) and stirred for 16 h. To this reaction was addedaqueous hydrochloric acid (1M, 30 ml). The solvent was evaporated andthe residue diluted in EtOAc (100 ml). This was washed with H₂O (3×20ml) and brine (10 ml). The organic layer was dried (MgSO₄) andconcentrated to yield a solid. This material was purified by reversephase HPLC (90% to 5% 0.02M ammonium hydroxide/acetonitrile) to yieldthe title compound as a solid. Yield: 30 mg.

MS APCI(+ve) 465 [M+H]⁺

¹H NMR δ_((CDCl3)) 7.93 (1H, m), 7.80 (1H, d), 7.55 (1H, m), 7.45 (1H,t), 7.20-7.40 (5H, m), 5.90 (1H, s), 5.20 (1H, bd), 4.32 (2H, s), 4.00(1H, bs), 3.60-3.70 (1H, m), 3.45-3.60 (1H, m), 1.21 (3H, d).

EXAMPLE 13N-(5-{[(2-(Benzylthio)-6{[(1R)-1-methylpropyl]amino}pyrimidin-4-yl)amino]sulfonyl}-4-methyl-1,3-thiazol-2-yl)acetamide

2-(Acetylamino)-1,3-thiazolesulfonyl chloride (0.19 g) was added to asolution of the subtitle product of Example 3 step ii) (0.2 g) inpyridine (4 ml) and N,N-dimethylaminopyridine (60 mg). The reactionmixture was stirred for 4 days. To this reaction more sulfonyl chloride(0.75 g) was added and stirred for 2 days. To this reaction was addedaqueous hydrochloric acid (1M, 20 ml) and THF (20 ml). This was stirredfor 18 h before the solvent was evaporated and the residue diluted inEtOAc (100 ml). This was washed with H₂O (3×20 ml) and brine (10 ml).The organic layer was dried (MgSO₄) and concentrated to yield a solid.This material was purified by reverse phase HPLC (90% to 5% 0.02Mammonium hydroxide/acetonitrile) to yield the title compound as a solid.Yield: 20 mg.

MS APCI(+ve) 509 [M+H]⁺

¹H NMR δ_((DMSO)) 7.20-7.37 (5H, m), 5.75 (1H, bs), 4.69 (1H, bs), 4.27(2H, bs), 3.31-3.39 (2H, m), 2.50 (3H, s), 2.12 (3H, s), 1.21 (3H, d).

EXAMPLE 14N-(2-(Benzylthio)-6-{[(1R)-1-methylpropyl]amino}pyrimidin-4-yl)-2-(methylsulfonyl)benzenesulfonamide

2-(Methylsulfonyl)benzenesulfonyl chloride (0.19 g) was added to asolution of the subtitle product of Example 3 step ii) (0.2 g) inpyridine (4 ml) and N,N-dimethylaminopyridine (59 mg). The reactionmixture was stirred for 4 days at room temperature. The solvent wasremoved, THF (2 ml) and sodium hydroxide (10%, 3 ml) added and stirringmaintained for 2 h. The volatiles were removed in vacuo and the aqueousresidue extracted with EtOAc (2×20 ml) and evaporated. To this residuewas added aqueous hydrochloric acid (1M, 30 ml) and THF (10 ml). Thiswas stirred at room temperature for 1 h. The mixture was extracted withEtOAc (2×30 ml). This was washed with H₂O (2×20 ml) and brine (20 ml).The organic layer was dried (MgSO₄) and concentrated to yield a solid.This material was purified by reverse phase HPLC (90% to 5% 0.02Mammonium hydroxide/acetonitrile) to yield the title compound as a solid.Yield: 30 mg.

MS APCI(+ve) 510 [M+H]⁺

¹H NMR δ_((CDCl3)) 8.31-8.34 (1H, dd), 8.23-8.26 (1H, dd),7.30-7.40 (2H,d), 7.18-7.30 (3H, m), 6.18 (1H, s), 4.90 (1H, d), 4.20 (2H, s), 4.00(1H, bs), 3.61-3.65 (1H, m), 3.45-3.60 (1H, m), 3.45 (3H, s), 1.21 (3H,d).

EXAMPLE 15N-(2-(Benzylthio)-6-{[(1R)-1-methylpropyl]amino}pyrimidin-4-yl)-4-(methylsulfonyl)benzenesulfonamide

The title compound was synthesised according to the procedure of Example14 using 4-methylsulfonylbenzenesulfonylchloride (0.19 g), the subtitleproduct of Example 3 step ii) (0.2 g) and N,N-dimethylaminopyridine (60mg) to yield the title compound as a white solid. Yield: 60 mg.

MS APCI(+ve) 510 [M+H]⁺

¹H NMR δ_((CDCl3)) 8.09-8.12 (1H, d), 7.97-8.00 (2H, d), 7.20-7.30 (5H,m), 5.90 (1H, s), 5.65 (1H, bs), 4.28 (2H, s), 4.00 (1H, bs), 3.69-3.71(1H, m), 3.49-3.60 (1H, m), 3.05 (3H, s), 1.17-1.19 (3H, d).

EXAMPLE 16N-(2-(Benzylthio)-6-{[(1R)-1-methylpropyl]amino}pyrimidin-4-yl)propane-1-sulfonamide

Propane-1-sulfonyl chloride (0.14 g) in DCM (1 ml) was added to asolution of the subtitle product of Example 3 step ii) (0.2 g) in DCM (3ml) and N,N-diisopropylethylamine (0.14 g) at 0° C. The reaction mixturewas stirred for 24 h at room temperature. To the reaction mixture moreN,N-diisopropylethylamine (0.14 g) was added and the reaction mixturewas stirred for an additional 24 h. The DCM was removed under reducedpressure and the residue dissolved in THF (2 ml). To this mixture sodiumhydroxide (10%, 2 ml) was added and stirred overnight. The reactionmixture was diluted with EtOAc (50 ml). The organic layer was separatedfrom the aqueous layer and evaporated to dryness. To the residue wasadded aqueous hydrochloric acid (1M, 30 ml) and THF (10 ml). This wasstirred at room temperature for 3 h. The mixture was extracted withEtOAc (2×50 ml). The organics were washed with brine (30 ml). Thecombined organic layers were dried (MgSO₄) and concentrated. Thismaterial was purified by reverse phase HPLC (90% to 5% 0.02M ammoniumhydroxide/acetonitrile) to yield the title compound as a white solid.Yield: 30 mg.

MS APCI(+ve) 397 [M+H]⁺

¹H NMR δ_((CDCl3)) 7.21-7.41 (5H, m), 5.94 (1H, s), 5.05 (1H, d) 4.30(2H, s), 4.10 (1H, bs), 3.68-3.73 (1H, m), 3.53-3.60 (1H, m), 3.16-3.21(2H, t), 1.77-1.90 (2H, m), 1.21 (3H, d). 1.00 (3H, t).

EXAMPLE 17N-(2-(Benzylthio)-6-{[(1R)-1-methylpropyl]amino}pyrimidin-4-yl)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide

3-Chloro-1,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (0.34 g) was addedto the subtitle product of Example 3 step ii) (0.1 g) in pyridine (1 ml)and N,N-dimethylaminopyridine (30 mg). The reaction mixture was stirredovernight at room temperature. To this reaction was addedtetrabutylammonium fluoride (4 ml, 1M in THF) and stirred for 3 h. Tothis mixture was added aqueous hydrochloric acid (30 ml, 1M) andextracted with EtOAc (2×30 ml) then brine (20 ml). The combined organiclayer was dried (MgSO₄) and concentrated. This material was purified bycolumn chromatography (EtOAc/iso-hexane (1:1) to EtOAc) to afford thetitle compound as a white solid. Yield: 30 mg.

MS APCI(+ve) 484[M+H]⁺

¹H NMR δ_((CDCl3)) 7.22-7.37 (5H, m), 5.87 (1H, s), 4.95 (1H, br,s),4.27 (2H, m), 4.0 (1H, br. s), 3.80 (3H, s), 3.66-3.70 (1H, m),3.52-3.56 (1H, m), 2.44 (3H, s), 1.20 (3H, d).

EXAMPLE 18N-(2-(Benzylthio)-6-{[(1R)-1-methylpropyl]amino}pyrimidin-4-yl)-1,3,5-trimethyl-1H-pyrazole-4-sulfonamide

The title compound was synthesised according to the procedure of Example17 using 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride (0.30 g), thesubtitle product of Example 3 step ii) (0.1 g),N,N-dimethylaminopyridine (30 mg) and tetrabutylammonium fluoride (4 ml,1M in THF) to yield the title compound as a white solid. Yield: 20 mg.

MS APCI(+ve) 463[M+H]⁺

¹H NMR δ_((CDCl3)) 7.21-7.36 (5H, m), 5.79 (1H, s), 4.95 (1H, d), 4.27(2H, s), 4.0 (1H, br. s), 3.70 (3H, s), 3.64-3.68 (1H, m), 3.50-3.54(1H, m), 2.41 (3H, s), 2.39 (3H, s),1.20 (3H, d).

EXAMPLE 19N-{2-(Benzylthio)-6-[(2-hydroxyethyl)amino]pyrimidin-4-yl}methanesulfonamide

To the subtitle product of step iii) (0.20 g) was added ethanolamine(3.0 ml) and the reaction was heated at 100° C. for 1 h. To the reactionwas added EtOAc (50 ml) and H₂O (50 ml). The organic layer was separatedand washed with H₂O (2×20 ml) and brine (20 ml). The organic layer wasdried (MgSO₄), the solids were filtered and the solvent removed underreduced pressure to give a solid. This was purified by columnchromatography (EtOAc/iso-hexane 1:1) to yield the title compound as asolid. Yield: 30 mg.

MS APCI(+ve) 355[M+H]⁺

¹H NMR δ_((CDCl3)) 7.19-7.40 (5H, m), 5.91 (1H, s), 5.45 (1H, t), 4.33(2H, s), 3.77 (2H, t), 3.52 (2H, m), 3.13(3H, s).

The intermediates for this compound were prepared as follows:

i) 2-(Benzylthio)pyrimidine-4,6-diol

A solution of sodium hydroxide (3.30 g) in ethanol/H₂O (60 ml/60 ml) wasadded to 2-mercaptopyrimidine-4,6-diol (10.00 g) and the mixture stirredfor 10 min. Benzyl bromide (13.45 g) was then added dropwise and themixture heated at 60° C. for 2 h. The reaction was cooled to 0° C. for 1h before the precipitate was filtered and washed with H₂O (100 ml) andthen dried in vacuo to afford the subtitle compound as a cream solid.Yield: 15.0 g.

¹H NMR δ_((DMSO)) 7.41-7.46 (2H, m), 7.20-7.40 (4H, m), 4.39 (2H, s).

ii) 2-(Benzylthio)-4,6-dichloropyrimidine

N,N-Dimethylaniline (7 ml) was added to the slurry of the the subtitleproduct of step i) (5.0 g) in phosphorus oxychloride (35 ml) and heatedat reflux for 10 h. The reaction was allowed to cool and excessphosphorus oxychloride was removed in vacuo before pouring onto ice.This mixture was extracted with EtOAc (200 ml) and washed with brine(2×100 ml), dried (MgSO₄) and concentrated in vacuo to afford the crudeproduct. This crude product was purified by column chromatography(EtOAc/iso-hexane (10 to 20%)) to yield the title compound. Yield: 4.10g.

¹HNMR δ_((CDCl3)) 7.40-7.42 (2H, m), 7.20-7.30 (4H, m), 4.38 (2H, s).

iii) N-[2-(Benzylthio)-6-chloropyrimidin-4-yl]methanesulfonamide

To methane sulphonamide (1.47 g) in DMF (30 ml) was added 60% sodiumhydride (0.59 g) at room temperature and stirred for 1 h. To thismixture was then added the subtitle product of step ii) and the mixturestirred at room temperature for 6 h. To the reaction mixture was addedEtOAc (50 ml) and aqueous hydrochloric acid (50 ml, 1M). The organiclayer was separated and washed with brine (20 ml), combined, dried(MgSO₄) and evaporated to dryness under reduced pressure. The residuewas purified by column chromatography (20 to 50% EtOAc/iso-hexane) toafford the subtitle compound as a yellow oil. Yield: 1.60 g.

MS APCI (+ve) 330 [M+H]⁺

¹H NMR δ_((DMSO)) 7.40-7.42 (2H, d), 7.20-7.40 (3H, m), 6.70 (1H, s),4.38 (2H, s), 3.30 (3H, s).

EXAMPLE 20N-(2-(Benzylthio)-6-{[(1R)-1-(hydroxymethyl)propyl]amino}pyrimidin-4-yl)methanesulfonamide

To the subtitle product of Example 19 step iii) (0.20 g) in NMP (1 ml)was added (2R)-2-aminobutan-1-ol (1.0 g) and the reaction was heated at100° C. for 2 days. To the reaction was added EtOAc (50 ml) and H₂O (50ml). The organic layer was separated and washed with H₂O (2×20 ml) andbrine (20 ml). The organic layer was combined, dried (MgSO₄) and thesolvent removed under reduced pressure to afford a solid. This waspurified by column chromatography (EtOAc/iso-hexane 1:1) to give thetitle compound as a solid. Yield: 15 mg.

MS APCI(+ve) 382 [M+H]⁺

¹H NMR δ_((DMSO)) 7.2-7.40 (2H, m), 7.20-7.30 (3H, m), 5.80 (1H, bs),4.80 (1H, bs), 4.30 (2H, s), 3.85 (1H, bs), 3.30-3.45 (2H, m),3.20 (3H,s), 1.41-1.64 (1H, m), 1.3-1.42 (1H, m), 0.83 (3H, t).

EXAMPLE 21N-(2-(Benzylthio)-6-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-pyrimidin-4-yl)methanesulfonamide

To a solution of the subtitle product of Example 19 step iii) (0.20 g)in NMP (0.5 ml) was added 2-aminopropane-1,3-diol (11.0 g) and thereaction was heated at 100° C. for 2 days. To the reaction was addedEtOAc (50 ml) and H₂O (50 ml). The organic layer was separated andwashed with H₂O (2×20 ml) and brine (20 ml). The organic layer was dried(MgSO₄) and the solvent removed under reduced pressure to give a solid.This was purified by column chromatography (1:1 EtOAc/iso-hexane thenEtOAc) to give the title compound as a solid. Yield: 20 mg.

MS APCI(+ve) 385 [M+H]⁺

¹H NMR δ_((DMSO)) 7.40-7.42 (2H, m), 7.20-7.30 (3H, m), 5.85 (1H, s),4.63 (1H, s), 4.32 (2H, s), 3.40 (4H, bs),3.20 (3H, s).

EXAMPLE 22N-(2-(Benzylthio)-6-{[(2R)-2-hydroxypropyl]amino}pyrimidin-4-yl)methanesulfonamide

To the subtitle product of Example 19 step iii) (0.20 g) in NMP (2 ml)was added (2R)-1-amino-2-propanol (0.46 g) and the reaction was heatedat 80° C. for 6 h. To the reaction was added EtOAc (50 ml) and H₂O (20ml). This solution was acidified with aqueous hydrochloric acid. Theorganic layer separated and washed with H₂O (2×20 ml), brine (20 ml) andthe organic layer was dried (MgSO₄) and the solvent removed underreduced pressure to give a solid. This material was purified by reversephase HPLC (90% to 5% 0.02M ammonium hydroxide/acetonitrile) to yieldthe title compound as a solid. Yield: 20 mg.

MS APCI(+ve) 370[M+H]⁺

¹HNMR δ_((CDCl3)) 7.2-7.47 (5H, m), 5.90 (1H, s), 5.40 (1H, bs), 4.32(2H, s), 3.90-4.10 (1H, m), 3.40-3.50 (1H, m), 3.21 (1H, m), 3.10 (3H,bs), 1.20 (3H, d).

EXAMPLE 23N′-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-N,N-dimethylsulfamide

To the subtitle product of step i) (0.20 g) was added (R)-alaninol (2.0ml) and the mixture heated at 80° C. for 2 days. The reaction mixturewas diluted in EtOAc (50 ml) and acidified with aqueous hydrochloricacid (1M, 20 ml). The aqueous was extracted further with EtOAc (50 ml).The combined organic layers were washed with H₂O (3×20 ml) and brine (20ml). The organic layer separated and further washed with H₂O (2×20 ml),brine (20 ml) and the organic layer was dried (MgSO₄) and the solventremoved under reduced pressure to give a solid. This material waspurified by reverse phase HPLC (90% to 5% 0.02M ammoniumhydroxide/acetonitrile) to yield the title compound as a solid. Yield:20 mg.

MS APCI(+ve) 398[M+H]⁺

¹H NMR δ_((CDCl3)) 7.2-7.40 (5H, m), 5.92 (1H, s), 4.98 (1H, bd), 4.32(2H, s), 4.07 (1H, bs), 3.68-3.75 (1H, m), 3.50-3.60 (1H, m), 2.87 (6H,s), 1.20 (3H, d).

The intermediates for the title compound were prepared as follows:

i) N′-[2-(Benzylthio)-6-chloropyrimidin-4-yl]-N,N-dimethylsulfamide

To N,N-dimethylsulphonamide (11.0 g) in DMF (10 ml) was added 60% sodiumhydride (0.22 g) at room temperature and the reaction heated to 50° C.for 1 h. This mixture was then allowed to cool to room temperature andthe subtitle product of Example 19 step ii) was added in DMF (1 ml). Tothe reaction mixture was added EtOAc (50 ml) and aqueous hydrochloricacid (50 ml, 1M). The organic layer was separated and washed with brine(20 ml). The organic layer was dried (MgSO₄) and evaporated to drynessunder reduced pressure. The residue was purified by columnchromatography (EtOAc/iso-hexane 1:4) to afford the title compound as ayellow gum. Yield: 0.48 g.

MS APCI (+ve) 359 [M+H]⁺

¹H NMR δ_((CDCl3)) 7.40-7.42 (2H, m), 7.20-7.40 (3H, m), 6.80 (1H, s),4.38 (3H, s), 2.92 (6H, s).

EXAMPLE 24N-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-1-methyl-2-oxoindoline-6-sulfonamide

1-Methyl-2-oxoindoline-5-sulfonyl chloride (0.74 g) was added to thecooled solution of the subtitle product of Example 3 step ii) (0.25 g)in pyridine (5 ml) and N,N-dimethylaminopyridine (75 mg). The reactionmixture was stirred for 3 days at room temperature. To this mixture wasadded aqueous hydrochloric acid (30 ml, 1M) and extracted with EtOAc(2×30 ml), brine (20 ml). The organic layer was dried (MgSO₄) andconcentrated. This material was purified by reverse phase HPLC (90% to5% 0.02M ammonium hydroxide/acetonitrile) to yield the title compound asa solid. Yield: 10 mg.

MS APCI(+ve) 500[M+H]⁺

¹H NMR δ_((DMSO)) 7.80 (1H, d), 7.70 (1H, s), 7.19-7.32 (5H, m), 7.06(1H, d), 5.82 (1H, s), 4.65 (1H, t), 4.20 (2H, s), 3.95 (1H, bs), 3.57(2H, s), 3.20-3.41 (2H, m), 3.10 (3H, s), 1.21 (3H, d).

EXAMPLE 251-{[(2-(benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)amino]sulfonyl}-N,N-dimethyl-L-prolinamide

To the subtitle product of step iv) (0.50 g) was added (R)-alaninol (2ml) and the mixture heated at 80-90° C. for 3 days. The reaction mixturewas taken in EtOAc (1 L) and acidified with aqueous hydrochloric acid(1M, 20 ml). The aqueous was evaporated to give a residue which waspurified by column chromatography (2% methanol/EtOAc) to give the titlecompound which was further purified by reverse phase HPLC (90% to 5%0.02M ammonium hydroxide/acetonitrile) to afford the title compound as awhite solid. Yield: 20 mg.

MS APCI(+ve) 495[M+H]⁺

¹H NMR δ_((DMSO)) 7.39-7.42 (2H, m), 7.19-7.32 (3H, m), 5.70 (1H, s),5.16 (1H, bs), 4.70 (1H, t), 4.30 (2H, m), 4.32 (2H, s), 3.38-3.45 (1H,m), 3.20-3.38 (3H, m), 3.04 (3H, s), 2.80 (3H, s), 1.95-2.10 (1H, m),1.80-1.92 (1H, m), 1.62-1.80 (2H, m), 1.07 (3H, d).

The intermediates for this compound were prepared as follows:

i) 1-(tert-Butoxycarbonyl)-N,N-dimethyl-L-prolinamide

To 1-(tert-butoxycarbonyl)-L-proline (5.0 g) in DCM (50 ml) at 5° C. wasadded dicyclohexylcarbodiimide (5.22 g) and N-hydroxysuccinimide (2.91g). The mixture was stirred at this temperature for 16 h. The solid wasfiltered and the filtrate cooled to 5° C. To this mixture was addedtriethylamine (9.80 ml) and dimethylamine hydrochloride (2.80 g). Themixture was stirred at room temperature for 2 days. H₂O (50 ml) wasadded and the phases were separated and the organics were washed withsaturated sodium carbonate (2×20 ml) and brine (20 ml). This was thendried (MgSO₄) and evaporated to dryness to afford the title compound asa white solid. Yield: 6.0 g.

¹H NMR δ_((CDCl3)) 4.62-4.70 (½H, m), 4.50-4.60 (½H, m), 3.38-3.65 (2H,m), 3.15 (3H, 2s), 2.98 (3H, 2s), 1.90-2.21 (2H, m),1.78-1.90 (2H,m),1.40-1.42 (9H, 2s).

ii) N,N-Dimethyl-L-prolinamide hydrochloride

To the subtitle product of step i) (5.0 g) was added hydrochloric acid(20 ml, 4M). The mixture was stirred at room temperature for 3 h beforethe solvent was evaporated to afford the subtitle compound as acolourless solid. Yield: 3.50 g

¹H NMR δ_((DMSO)) 9.90 (1H,s, br), 8.40 (1H, s, br), 4.50-4.56 (1H, m),3.00-3.30 (2H, m), 3.04 (3H, s), 2.90 (3H, s), 2.21-2.44 (1H, m),1.71-1.95 (3H, m).

iii) 1-(Aminosulfonyl)-N,N-dimethyl-L-prolinamide

To a solution of the subtitle product of step ii) (3.70 g) in dioxane(50 ml) was added triethylamine (2.02 g) and sulfamide (9.96 g). Themixture was heated at reflux for 3 days before the reaction mixture wascooled, filtered and washed with methanol (50 ml). The solvent wasevaporated and the residue purified by column chromatography (2%methanol/EtOAc) to afford the subtitle compound as an oil. Yield: 1.70g.

MS APCI(+ve) 222[M+H]⁺

¹H NMR δ_((DMSO)) 6.63 (2H, bs), 4.58-4.61 (1H, m), 3.18-3.34 (2H, m),3.04 (3H, s), 2.80 (3H, s), 2.00-2.10 (1H, m),1.68-1.92 (3H, m).

iv)1-({[2-(Benzylthio)-6-chloropyrimidin-4-yl]amino}sulfonyl)-N,N-dimethyl-L-prolinamide

60% Sodium hydride (0.42 g) was added to a solution of the subtitleproduct of step iii) (1.0 g) in DMF (10 ml) at 0° C. This mixture wasstirred for 1 h before the addition of the subtitle product of Example19 step ii) (1.60 g) in DMF (5 ml) was added dropwise. The mixture wasallowed to reach room temperature and stirred for 3 days. To the mixturewas added aqueous hydrochloric acid (1M) and extracted with EtOAc (2×100ml). The organic layer was washed with H₂O (2×50 ml), the organic layercollected and concentrated causing the subtitle compound to precipitateout. This was filtered and washed with EtOAc (20 ml). Yield: 1.10 g.

MS APCI(+ve) 455[M+H]⁺

¹H NMR δ_((CDCl3))

) 7.42-7.46 (2H, m), 7.20-7.32 (3H, m), 7.02 (1H, s), 4.85-4.89 (1H, m),4.32 (2H, s), 3.55-3.60 (2H, m), 3.05 (3H, s), 3.02 (3H, s), 2.33-2.4(1H, m), 1.94-2.13 (3H, m).

EXAMPLE 261-{[(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)amino]sulfonyl}-N,N-dimethyl-D-prolinamide

To the subtitle product of step iv) (1.0 g) was added R-alaninol (3 ml)and the mixture heated at 80-90° C. for 4 days. The reaction mixture wastreated with EtOAc (100 ml) and acidified with aqueous hydrochloric acid(1M, 100 ml). The aqueous was separated and evaporated to give a residuewhich was purified by column chromatography (10% methanol/EtOAc) to givethe title compound as a white solid. This material was further purifiedby reverse phase HPLC (90% to 5% 0.02M ammonium hydroxide/acetonitrile).Yield: 70 mg.

MS APCI(+ve) 495[M+H]⁺

¹H NMR δ_((DMSO)) 7.36-7.41 (2H, m), 7.20-7.30 (3H, m), 5.70 (1H, s),5.23 (1H, bd), 4.70 (1H, t), 4.27-4.37 (2H, m), 3.15-3.31 (4H, m), 3.04(3H, s), 2.80 (3H, s), 2.00-2.10 (1H, m),1.80-2.00 (1H, m), 1.62-1.80(2H, m), 1.07 (3H, d).

The intermediates for the above compound were prepared as follows:

i) 1-(Benzyloxycarbonyl)-N,N-dimethyl-D-prolinamide

The subtitle compound was prepared according to the method of Example 25step i) using 1-(benzyloxycarbonyl)-D-proline (3.90 g) in DCM (50 ml).Yield: 4.45 g.

MS APCI(+ve) 276[M+H]⁺

ii) N,N-Dimethyl-D-prolinamide

To the subtitle compound of step i) (4.45 g) was added palladiumhydroxide (0.20 g) and methanol (50 ml). The mixture was stirred under ahydrogen atmosphere (4 bar) at room temperature for 3 h before thecatalyst was filtered through celite and the solvent was evaporated toafford the subtitle compound as a solid. Yield: 2.25 g.

¹H NMR δ_((CDCl3)) 3.81-3.90 (1H, m), 3.13-3.22 (1H, m), 3.00 (3H, s),2.98 (3H, s), 2.74-2.87 (1H, m), 2.50 (1H, bs), 2.05-2.20 (1H, m),1.59-1.90 (3H, m).

iii) 1-(Aminosulfonyl)-N,N-dimethyl-D-prolinamide

To a solution of the subtitle compound of step ii) (2.20 g) in dioxane(25 ml) was added sulfamide (7.20 g) and the mixture heated at refluxfor 45 h. The reaction mixture was cooled and adsorbed on to silica geland then purified by column chromatography (5% methanol/EtOAc) to affordthe subtitle compound as an oil. Yield: 1.6 g.

MS APCI(+ve) 222[M+H]⁺

¹H NMR δ_((DMSO)) 6.63 (2H, bs), 4.58-4.61 (1H, m), 3.18-3.40 (2H, m),3.04 (3H, s), 2.80 (3H, s), 2.00-2.10 (1H, m), 1.70-2.00 (3H, m).

iv)1-({[2-(Benzylthio)-6-chloropyrimidin-4-yl]amino}sulfonyl)-N,N-dimethyl-D-prolinamide

60% Sodium hydride (0.42 g) was added to a solution of the subtitleproduct of step iii) (1.50 g) in DMF (20 ml) at 0° C. This mixture wasstirred for 1 h and then a solution of the subtitle product of Example19 step ii) (1.60 g) in DMF (5 ml) was added dropwise. The mixture wasallowed to reach room temperature and stirred there for 2 days. To themixture was added aqueous hydrochloric acid (100 ml) and the resultingprecipitate was filtered. This solid was then stirred with EtOAc (200ml) and filtered to afford the subtitle compound as a solid. Yield: 2.0g.

MS APCI(+ve) 456[M+H]⁺

¹H δ_((DMSO))

) 7.40-7.50 (2H, m), 7.20-7.40 (2H, m), 7.21-7.30 (1H, m) 6.70 (1H, s),5.10-5.20 (1H, m), 4.32 (2H, s), 3.20-3.40 (2H, m), 3.04 (3H, s), 2.80(3H, s), 2.00-2.10 (1H, m), 1.80-1.88 (1H, m), 1.70-1.88 (2H, m).

EXAMPLE 27N-(2-[(3-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)methanesulfonamide

Methanesulfonyl chloride (0.15 ml) was added to a solution of thesubtitle product of step iii) (0.40 g) and N,N-diiosopropylethylamine(0.53 ml) in DCM (15 ml) and stirring maintained for 30 min. A furtherportion of methanesulfonyl chloride (0.15 ml) andN,N-diiosopropylethylamine (0.53 ml) were added and stirring maintainedfor a further 30 min. The reaction solution was extracted with H₂O (2×20ml) and the organics dried (MgSO₄) and concentrated to yield a brownoil. The residue was diluted in THF (7 ml) and treated with aqueoussodium hydroxide solution (1.5 ml of a 2.5M solution) for 1 h at roomtemperature. The reaction mixture was acidified with 2M hydrochloricacid solution to pH 1 and stirring maintained for 1 h before the mixturewas neutralised with sodium hydroxide solution, concentrated onto silicagel and purified by column chromatography (Et₂O then EtOAc). The crudeproduct was then purified by reverse phase HPLC (acetonitrile/0.02Mammonium hydroxide (90% to 5% aqueous phase)) to yield the titlecompound as a white solid. Yield: 0.12 g.

MS APCI(+ve) 421 [M+H]⁺

¹H NMR δ_((DMSO)) 7.57 (1H, t), 7.48 (1H, t), 7.26 (1H, s), 7.17 (1H,t), 5.85 (1H, s), 4.71 (1H, s), 4.38 (2H, s), 3.98 (1H, s), 3.43-3.24(2H, m), 3.20 (3H, s), 1.05 (3H, d).

The intermediates for the above compound were prepared as follows:

i) 6-Amino-2-[(3-chloro-2-fluorobenzyl)thio]pyrimidin-4(3H)-one

The subtitle compound was prepared according to the procedure of Example1 step i) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate(8.4 g) with 3-chloro-2-fluorobenzyl bromide (11.0 g) to afford thesubtitle compound as a white solid. Yield: 14.1 g.

MS APCI(+ve) 286 [M+H]⁺

ii) 6-Chloro-2-[(3-chloro-2-fluorobenzyl)thio]pyrimidin-4-amine

The subtitle compound was prepared from the product of step i) (2.00 g)according to the procedure of Example 1 step ii) to afford the subtitleproduct as a green foam which was used directly in the next step.

MS: APCI(+ve) 304 [M+H]⁺

iii)N-((1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-[(3-chloro-2-fluoro-benzyl)thio]pyrimidine-4,6-diamine

N,N-Diisopropylethylamine (5.2 ml) was added to a solution of(R)-alaninol (2.56 ml) and the subtitle product of step ii) in NMP (35ml) and stirred at 100° C. for 24 h and then 140° C. for 24 h. Aftercooling to ambient temperature imidazole (2.60 g) and a solution oftert-butyldimethylsilyl chloride (2.60 g) in THF (10 ml) were added andstirring maintained for 1 h. The volatiles were removed in vacuo and theresidue was purified by column chromatography (1:1 Et₂O/iso-hexane) toafford the subtitle compound as a yellow oil. Yield: 1.70 g.

MS: APCI(+ve) 457 [M+H]⁺

EXAMPLE 28N-(2-[(2,3-Dichlorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)methanesulfonamide

The title compound was synthesised from the subtitle product of stepiii) (0.4 g) according to the procedure of Example 27 to afford thetitle compound as a white solid. Yield: 0.15 g.

MS APCI(+ve) 437 [M+H]⁺

¹H NMR δ_((DMSO)) 10.55 (1H, s), 7.66 (1H, d), 7.55 (1H, dd), 7.31 (1H,t), 7.26 (1H, s), 5.78 (1H, s), 4.71 (1H, s), 4.46 (2H, s), 3.99 (1H,s), 3.41-3.24 (2H, m), 3.20 (3H, s), 1.05 (3H, d).

The intermediates for the above compound were prepared as follows:

i) 6-Amino-2-[(2,3-dichlorobenzyl)thio]pyrimidin-4(3H)-one

The subtitle compound was prepared according to the procedure of Example1 step i) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate(2.22 g) with 2,3-dichlorobenzyl bromide (3.30 g) to afford the subtitlecompound as a white solid. Yield: 3.25 g.

MS APCI(+ve) 302 [M+H]⁺

ii) 6-Chloro-2-[(2,3-dichlorobenzyl)thio]pyrimidin-4-amine

The subtitle compound was prepared from the product of step i) (2.00 g)according to the procedure of Example 1 step ii) to afford the subtitleproduct as a green foam which was used directly in the next step.

MS: APCI(+ve) 320 [M+H]⁺

iii)N-((1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-[(2,3-dichlorobenzyl)-thio]pyrimidine-4,6-diamine

The subtitle compound was synthesised from the subtitle product of stepii) according to the procedure of Example 27 step iii). Yield: 0.4 g.

MS: APCI(+ve) 473 [M+H]⁺

EXAMPLE 29N-(2-[(3-Chlorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)methanesulfonamide

The title compound was prepared from the subtitle product of step iii)(0.4 g) according to the procedure of Example 27 as a white solid.Yield: 71 mg.

MS APCI(+ve) 403 [M+H]⁺

¹H NMR δ_((DMSO)) 7.52-7.17 (4H, m), 5.78 (1H, s), 4.70 (1H, t), 4.32(2H, dd), 3.97 (1H, s), 3.44-3.24 (2H, m), 3.18 (3H, s), 1.06 (3H, d).

The intermediates for the above compound were prepared as follows:

i) 6-Amino-2-[(3-chlorobenzyl)thio]pyrimidin-4(3H)-one

The subtitle compound was prepared according to the procedure of Example1 step i) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate(10.00 g) with 3-chlorobenzyl chloride (9.98 g) to afford the subtitlecompound as a white solid. Yield: 15.00 g.

MS APCI(+ve) 268 [M+H]⁺

ii) 6-Chloro-2-[(3-chlorobenzyl)thio]pyrimidin-4-amine

The subtitle compound was prepared from the product of step i) (2.00 g)according to the procedure of Example 1 step ii) to afford the subtitleproduct as a green foam which was used directly in the next step.

MS: APCI(+ve) 286 [M+H]⁺

iii)N-((1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-[(3-chlorobenzyl)thio]-pyrimidine-4,6-diamine

The subtitle compound was synthesised from the subtitle product ofExample 29 step ii) according to the procedure of Example 27 step iii).Yield: 0.4 g.

MS: APCI(+ve) 439 [M+H]⁺

EXAMPLE 30N-(2-[(2-Fluoro-4-methoxybenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)methanesulfonamide

The title compound was synthesised from the subtitle product of Example30 step iii) (0.4 g) according to the procedure of Example 27 as a whitesolid. Yield: 35 mg.

MS APCI(+ve) 403 [M+H]⁺

¹H NMR δ_((DMSO)) 7.45 (1H, t), 7.21 (1H, s), 6.81 (1H, dd), 6.73 (1H,dd), 5.77 (1H, s) 4.71 (1H, t), 4.27 (2H, s), 3.74 (3H, s), 3.44-3.21(2H, m), 3.20 (3H, s), 1.08 (3H, d).

The intermediates for the above compound were prepared as follows:

i) 6-Amino-2-[(2-fluoro-4-methoxybenzyl)thio]pyrimidin-4(3H)-one

The subtitle compound was prepared according to the procedure of Example1 step i) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate(1.86 g) with 2-fluoro-4-methoxybenzyl chloride (2.00 g) to afford thesubtitle compound as a white solid. Yield: 2.64 g.

MS APCI(+ve) 282 [M+H]⁺

ii) 6-Chloro-2-[(2-fluoro-4-methoxybenzyl)thio]pyrimidin-4-amine

The subtitle compound was prepared from the product of Example 30 stepi) according to the procedure of Example 1 step ii) to afford thesubtitle product as a green foam which was used directly in thesubsequent step.

MS: APCI(+ve) 300 [M+H]⁺

iii)N-((1R)-2-{[tert-Butyl-(dimethyl)silyl]oxy}-1-methylethyl)-2-[(2-fluoro-4-methoxy-benzyl)thio]pyrimidine-4,6-diamine

The subtitle compound was synthesised from the subtitle product of stepii) according to the procedure of Example 27 step iii). Yield: 0.4 g.

MS: APCI(+ve) 453 [M+H]⁺

EXAMPLE 31N-(2-[(3-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)piperazine-1-sulfonamide

The subtitle product of step ii) (0.7 g) was diluted in (R)-alaninol (4ml) and heated at 80° C. for 48 h. The product was purified through aplug of silica gel (1:1 EtOAc/isohexane then 90:9:1EtOAc/methanol/N,N-diethylisopropylamine). The crude product was dilutedin 1,4-dioxane (40 ml) and treated with HCl/1,4-dioxane (0.5 ml of a 4Msolution) for 1 h before concentrating in vacuo and purifying the crudeproduct by reverse phase HPLC (acetonitrile/0.02M ammonium hydroxide(90% to 5% aqueous phase)) to yield the title product as a white solid.Yield: 49 mg.

MS: APCI(+ve) 491 [M+H]⁺

¹H NMR δ_((DMSO)) 7.59 (1H, t), 7.46 (1H, t), 7.15 (1H, t), 7.06 (1H,s), 5.85 (1H, s), 4.69 (1H, t), 4.36 (2H, t), 3.89 (1H, s), 3.42-3.23(2H, m), 3.05 (4H, m), 2.71 (4H, m), 1.05 (3H, d).

The intermediates for the above compound were prepared as follows:

i) tert-Butyl 4-(aminosulfonyl)piperazine-1-carboxylate

A mixture of tert-butyl-4-piperazine-1-carboxylate (1.47 g) andsulfamide (5.25 g) in 1,4-dioxan (50 ml) were heated at reflux for 48 h.The volatiles were removed in vacuo and the residue partitioned betweenEtOAc (100 ml) and H₂O (100 ml). The organics were recovered and theaqueous extracted further with EtOAc (3×100 ml). The organics were thencombined, dried (MgSO₄) and concentrated. The crude material wastriturated with diethyl ether and filtered to provide the subtitlecompound as a white solid. Yield: 1.91 g

¹H NMR δ_((DMSO)) 6.80 (2H, s), 3.40 (4H, t), 2.90 (4H, t), 1.41 (9H,s).

ii) 2-[(3-Chloro-2-fluorobenzyl)thio]pyrimidine-4,6-diol

The subtitle compound was prepared by the method of Example 19 step i)using 2-mercaptopyrimidine-4,6-diol (20.0 g) and 3-chloro-2-fluorobenzylbromide to afford the subtitle compound as a white solid. Yield: 36.2 g.

MS: APCI(+ve) 287 [M+H]⁺

iii) 4,6-Dichloro-2-[(3-chloro-2-fluorobenzyl)thio]pyrimidine

N,N-Dimethylaniline (50 ml) was added to a slurry of the the subtitleproduct of step ii) (36.2 g) in phosphorus oxychloride (200 ml) andheated at reflux for 10 h. The reaction was allowed to cool and theexcess phosphorus oxychloride removed in vacuo before pouring onto ice.This mixture was extracted with EtOAc (400 ml) and washed with brine(2×10 ml), the organics collected, dried (MgSO₄) and concentrated invacuo to afford the crude product. This crude product was purified byflash chromatography (EtOAc/isohexane (2 to 5%)) to yield the subtitlecompound as an oil. Yield: 6.2 g.

MS: APCI(−ve) 322 [M−H]⁺

iv)N-{6-Chloro-2-[(3-chloro-2-fluorobenzyl)thio]pyrimidin-4-yl}piperazine-1-sulfonamide

60% Sodium hydride (0.22 g) was added to a solution of the subtitleproduct of step i) (1.78 g) in DMF (10 ml) at 0° C. The reaction wasremoved from the cooling bath and stirred for 1 h before adding thesubtitle product of step iii) (1.46 g) as a solution in DMF (5 ml). Thereaction was stirred overnight before concentrating in vacuo. Theresidue was partitioned between H₂O (50 ml) and EtOAc (50 ml) and theorganics recovered, dried (MgSO₄) and concentrated in vacuo. The crudeproduct was purified by flash column chromatography (20% then 30%EtOAc/iso-hexane) to yield the subtitle compound as a white solid.Yield: 0.7 g.

¹HNMR δ_((DMSO)) 11.64 (1H, s), 7.63-7.47 (2H, m), 7.19 (1H, t), 6.70(1H, s), 4.47 (2H, s), 3.35 (8H, s), 1.40 (9H, s).

EXAMPLE 32N-(2-[(3-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-1-(hydroxymethyl)propyl]amino}-pyrimidin-4-yl)piperazine-1-sulfonamide

The subtitle product of step iv) (0.27 g) was diluted in trifluoroaceticacid (2 ml) and stirred for 20 min before removing the volatiles invacuo. The residue was diluted in DCM (20 ml) and the volatiles againremoved in vacuo. The title product was purified by reverse phase BPLC(acetonitrile/0.02M ammonium hydroxide (90% to 5% aqueous phase)) toyield the title compound as a white solid. Yield: 0.11 g.

MS: APCI(+ve) 505 [M+H]⁺

¹H NMR δ_((DMSO)) 7.59 (1H, t), 7.47 (1H, t), 7.15 (1H, t), 7.10 (1H,s), 5.89 (1H, s), 4.64 (1H, s), 4.36 (2H, s), 3.43-3.24 (2H, m), 3.08(4H, m), 2.72 (4H, d), 1.60 (1H, m), 1.36 (1H, m), 0.82 (3H, t).

The intermediates for the above compound were prepared as follows:

i)tert-Butyl-4-[({6-chloro-2-[(3-chloro-2-fluorobenzyl)thio]pyrimidin-4-yl}{[2-(trimethylsilyl)ethoxy]methyl}amino)sulfonyl]piperazine-1-carboxylate

60% Sodium hydride (44 mg) was added to a solution of the subtitleproduct of Example 31 step iii) (0.40 g) in DMF (6 ml) at 0° C. Stirringwas maintained for 10 min before the addition of[2-(chloromethoxy)ethyl](trimethyl)silane. The reaction was removed fromthe cooling bath and stirred for 2 h before the reaction was partitionedbetween H₂O (30 ml) and EtOAc (50 ml). The aqueous was extracted furtherwith EtOAc (2×50 ml), the organics combined, dried (MgSO₄) andconcentrated to afford the subtitle product as a colourless oil. Yield:0.60 g.

MS: APCI(+ve) 682 [M+H]⁺

ii)tert-butyl-4-[((2-[(3-chloro-2-fluorobenzyl)thio]-6-{[(1R)-1-(hydroxymethyl)-propyl]amino}pyrimidin-4-yl){[2-(trimethylsilyl)ethoxy]methyl}amino)sulfonyl]-piperazine-1-carboxylate

The subtitle product of step i) (0.60 g) was diluted in(2R)-2-aminobutan-1-ol (2 ml) and heated at 80° C. for 18 h. Thesubtitle compound was recovered as a colourless oil by flash columnchromatography (EtOAc/iso-hexane mixtures). Yield: 0.40 g.

MS: APCI(+ve) 735 [M+H]⁺

EXAMPLE 33N′-(2-[(3-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)-N,N-dimethylsulfamide

The subtitle product of step i) (0.7 g) was diluted in (R)-alaninol (4ml) and heated at 80° C. for 48 h before partitioning between EtOAc/1Mhydrochloric acid. The aqueous was further extracted with EtOAc (3×),the organics combined, washed with brine, dried (MgSO₄) andconcentrated. The product was purified by column chromatography (25%,40% EtOAc/iso-hexane then EtOAc) to yield the title compound as acolourless oil. Yield: 0.13 g.

MS: APCI(+ve) 450 [M+H]⁺

¹H NMR δ_((DMSO)) 10.43 (1H, s), 7.57 (1H, t), 7.47 (1H, dd), 7.29 (1H,s), 7.16 (1H, t), 5.87 (1H, s), 4.70 (1H, s), 4.37 (2H, t), 4.04 (1H,s), 3.43-3.24 (2H, m), 2.77 (6H, s), 1.05 (3H, d).

The intermediates for the above compound were prepared as follows:

i)NA-{6-chloro-2-[(3-chloro-2-fluorobenzyl)thio]pyrimidin-4-yl}-N,N-dimethyl-sulfamide

60% Sodium hydride (0.48 g) was added to a solution ofN,N-dimethylsulfamide (1.05 g) in DMF (15 ml) and stirring maintainedfor 10 min before the addition of the subtitle product of Example 31step iii) (3.56 g). The reaction was stirred for 18 h before thereaction was partitioned between H₂O (30 ml) and EtOAc (50 ml). Theaqueous was extracted further with EtOAc (2×50 ml) the organicscombined, washed with H₂O (100 ml), brine (50 ml), dried (MgSO₄) andconcentrated. The crude product was purified by flash columnchromatography (20% then 30% EtOAc/isohexane) to yield the subtitlecompound as a white solid. Yield: 1.57 g.

¹H NMR δ_((DMSO)) 11.49 (1H, s), 7.56 (1H, t), 7.51 (1H, t), 7.19 (1H,t), 6.69 (1H, s), 4.44 (2H, s), 2.83 (6H, s).

EXAMPLE 34N-(2-[(3-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-2-(dimethylamino)ethanesulfonamide

The subtitle product of step iv) (0.7 g) was diluted in (R)-alaninol(2.25 ml) and heated at 80° C. for 48 h. The product was purified byreverse phase HPLC (acetonitrile/0.02M ammonium hydroxide (90% to 5%aqueous phase)) to yield the title compound as a white solid. Yield: 46mg.

MS: APCI(+ve) 478 [M+H]⁺

¹H NMR δ_((DMSO)) 7.6 (1H, t), 7.43 (1H, t), 7.15 (1H, t), 6.64 (1H, br.s), 5.54 (1H, s), 4.35 (2H, s), 3.80 (1H, s), 3.41-3.11 (6H, m), 2.09(6H, s) and 1.08 (3H, d).

The intermediates for the above compound were prepared as follows:

i) Sodium 2-(dimethylamino)ethanesulfonate

Sodium ethylenesulfonate (18.2 ml, 25% aqueous solution w/w) anddimethylamine (4.43 ml, 40% aqueous solution w/w) were heated in asealed finger tube at 105° C. for 48 h before concentrating in vacuo toyield the subtitle compound as a white solid. Yield: 9.80 g.

¹H NMR δ_((CD3OD)) 3.05 (2H, m), 2.84 (2H, m) and 2.30 (6H, s).

ii) 2-(Dimethylamino)ethanesulfonyl chloride

Phosgene (12 ml, 1M in toluene) was added to a solution of the subtitleproduct of step i) in DCM (20 ml) and DMF (2.5 ml) and stirred for 3 hbefore concentrating in vacuo to afford the subtitle compound as an oilthat was used directly in the next step.

¹H NMR δ_((CD3OD)) 3.30 (2H, m), 2.80 (2H, m) and 2.31 (6H, s).

iii) 2-(Dimethylamino)ethanesulfonamide

Ammonia was cautiously added to a cooled solution of the subtitleproduct of step ii) in THF (50 ml) and stirring maintained until all ofthe ammonia had evaporated before filtering off the product as a whitesolid. Yield: 0.88 g.

¹H NMR δ_((CDCl3)) 3.20 (2H, t), 2.86 (2H, m) and 2.30 (6H, s).

iv)N-{6-Chloro-2-[(3-chloro-2-fluorobenzyl)thio]pyrimidin-4-yl}-2-(dimethylamino)ethanesulfonamide

The subtitle compound was prepared by the method of Example 33 step i)from the reaction of the subtitle product of step iii) (0.8 g) and thesubtitle product of Example 31 step iii) (1.1 g) and used directly inthe following step. Yield 0.7 g

¹H NMR δ_((CDCl3)) 7.48 (1H, t), 7.31 (1H, t), 7.02 (1H, t), 6.87 (1H,s), 4.38 (2H, s), 3.21 (2H, m), 2.83 (2H, m), 2.32 (3H, s), 2.25 (3H,s).

EXAMPLE 35N-(2-[(3-chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-4-methylpiperazine-1-sulfonamide

A solution of the product from step iv) (1.5 g) in (R)-alaninol (3 ml)was heated at 80° C. for 4 days. The resulting mixture was diluted withacetonitrile (5 ml) and purified by reverse phase HPLC (50% to 5% 0.02Mammonium hydroxide/methanol) to yield the title compound as a whitesolid. Yield: 1.0 g.

MS APCI(+ve) 506 [M+H]⁺

¹H NMR δ_((DMSO)) 10.60 (1H, bd), 7.60 (1H, m), 7.55 (1H, m), 7.47 (1H,bs), 7.19 (1H, t), 5.88 (1H, s), 4.72 (1H, t), 4.37 (2H, s), 3.40 (1H,m), 3.30 (2H, m), 3.10 (4H, m), 2.30 (4H, m), 2.10 (3H, s), 1.05 (3H,d).

The intermediates for this compound were prepared as follows:

i) 4-Methyl-1-piperazinesulfonamide

N-Methyl piperazine (5 ml) and sulfamide (11.26 g) in 1,4-dioxane (100ml) were heated at reflux for 48 h. The solvent was evaporated underreduced pressure and the resulting solid dissolved in a mixture ofmethanol and water and applied to a plug of SCX-silica followed byfurther elution with aqueous methanol. This was then followed by elutionwith 1M ammonia in methanol (×4) and these fractions collected andsolvent evaporated to dryness leaving a white solid. This was trituratedwith Et₂O and filtered leaving the subtitle compound as a white solid.Yield: 5.0 g.

¹H NMR δ_((DMSO)) 6.75 (2H, s), 2.90 (4H, m), 2.40 (4H, m), 2.20 (3H,s).

ii) 2-[(3-Chloro-2-fluorobenzyl)thio]-4,6-pyrimidinediol

To a slurry of 2-mercapto-4,6-pyrimidinediol (64.6 g) in ethanol (387ml) and H₂O (387 ml) was added sodium hydroxide (18 g) in H₂O (82 ml)causing almost a complete solution to form.2-Fluoro-3-chloro-benzylbromide (10 g) in ethanol (82 ml) was then addeddropwise over 30 min causing a thick precipitate to form. Stirring wascontinued for a further 4 h and the whole then cooled to 0° C. beforefiltering the white solid formed and then washing with water. Thecollected solid was dried in vacuo at 50° C. for 48 h leaving thesubtitle compound as a white solid. Yield: 125.7 g.

MS APCI(+ve) 287 [M+H]⁺

iii) 4,6-Dichloro-2-[(3-chloro-2-fluorobenzyl)thio]-pyrimidine

The subtitle product from step ii) (125.67 g) was added slowly tophosphorus oxychloride (1 L) over 10 min with stirring. After theaddition was complete, N,N-dimethylaniline (92 ml) was added portionwisewith care over 10 min causing a complete solution to form. This was thenstirred at 120° C. for 15 h. The cooled reaction mixture was then pouredonto crushed ice and extracted with EtOAc (×3). The organic phases werecombined, dried (MgSO₄) and the solvent evaporated leaving a brown oilwhich was purified by column chromatography (2% EtOAc/iso-hexane) toafford the subtitle compound as a white solid. Yield: 113 g.

¹H NMR δ_((CDCl3)) 7.41(1H, m), 7.30(1H, m), 7.0 (2H, m+s), 4.40(2H, s).

iv)N-[6-Chloro-2-[(3-chloro-2-fluorobenzyl)thio]-4-pyrimidinyl]-4-methyl-1-piperazinesulfonamide

To a solution of the subtitle product of step i) (2.0 g) in dry DMF (20ml) at 0° C. was added 60% sodium hydride (0.9 g) portionwise over 5min. After further stirring at 0° C. for 30 min the subtitle productfrom step iii) (3.6 g) in DMF (10 ml) was added and the whole allowed tostir at room temperature for 24 h. The reaction mixture was carefullyquenched with aqueous 2M hydrochloric acid until pH 7.4. The solvent wasevaporated to dryness and the residue dissolved in a mixture ofmethanol/EtOAc and applied to an SCX column followed by further elutionwith EtOAc. This was then followed by elution with EtOAc/triethylaminemixtures and these fractions evaporated to dryness. The subtitlecompound was obtained pure by trituration with Et₂O and filtration,leaving a white solid. Yield: 1.5 g.

MS APCI(+ve) 467 [M+H]⁺

EXAMPLE 36N-[2-[(3-Chloro-2-fluorobenzyl)thio]-6-[(2-hydroxy-1-methylethyl)amino]-4-pyrimidinyl]-4-morpholinesulfonamide

The title compound was prepared from the product of step ii) (1.0 g) and(R)-alaninol (5 ml) according to the procedure used in Example 35 as awhite solid. Yield: 0.68 g.

MS APCI(+ve) 493 [M+H]⁺

¹H NMR δ_((DMSO)) 10.60 (1H, bs), 7.60 (1H, m), 7.50 (1H, m), 7.30 (1H,bs), 7.19 (1H, m), 5.90 (1H, s), 4.70 (1H, m), 4.20 (2H, s), 4.0 (1H,m), 3.80 (4H, m), 3.40 (2H, m), 3.10 (4H, m), 1.10 (3H, d).

The intermediates for this compound were prepared as follows

i) 4-Morpholinesulfonamide

Morpholine (5 ml) and sulfamide (11 g) in 1,4-dioxane (100 ml) wereheated at reflux for 48 h. The solvent was evaporated under reducedpressure and the resulting solid partitioned between EtOAc and water.The organic phase was collected and the aqueous phase was furtherextracted with EtOAc (×4). The combined organic extracts were dried(MgSO₄) and the solvent removed in vacuo. The solid residue wastriturated with Et₂O and filtered to give the subtitle compound as awhite crystaline solid. Yield: 2.1 g.

¹H NMR δ_((DMSO)) 6.82 (2H, s), 3.66 (4H, m), 2.90 (4H, m).

ii)N-[6-chloro-2-[(3-chloro-2-fluorobenzyl)thio]-4-pyrimidinyl]-4-morpholinesulfonamide

To a solution of the product of step i) (2.1 g) in dry DMF (20 ml) at 0°C. under nitrogen was added 60% sodium hydride (1.1 g) portionwise over5 min. After further stirring at 0° C. for 30 min the product fromExample 31 step iii) (4 g) in DMF (10 ml) was added and the wholeallowed to further stir at room temperature for 24 h. The reactionmixture was carefully quenched with aqueous 2M hydrochloric acid untilpH 7.4. The solvent was evaporated to dryness and the residuepartitioned between EtOAc and brine. The organic phase was collected,dried (MgSO₄) and the solvent removed in vacuo to afford the subtitlecompound as a gummy solid. Yield: 1.3 g.

MS APCI(+ve) 454 [M+H]⁺

EXAMPLE 37N-[2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-6[(2-hydroxy-1-methylethyl)amino]-4-pyriniidinyl]-1,2-dimethyl-1H-imidazole-4-sulfonamide

To a solution of the product from Example 27 step iii) (1.3 g) in drypyridine (10 ml) and 4 N,N-dimethylaminopyridine (0.48 g) under nitrogenwas added 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (1.0 g). Thereaction mixture was heated at 55° C. for 5 days. The cooled reactionmixture was partitioned between EtOAc and 1M hydrochloric acid. Theorganic phases were collected, dried (MgSO₄) and the solvent evaporatedto dryness. The resulting gum was dissolved in acetonitrile (15 ml) andtreated with 2M hydrochloric acid (5 ml) and the whole stirred at roomtemperature for 15 min. The reaction mixture was evaporated to drynessleaving a gummy residue. Purification by column chromatography(DCM/methanol/acetic acid 190:10:1) afforded the title compound as awhite solid. Yield: 1.0 g.

MS APCI(+ve) 501 [M+H]⁺

¹H NMR δ_((DMSO)) 7.85 (1H, bs), 7.50 (2H, m), 7.18 (1H, m), 5.91(1H,m), 4.36 (2H, s), 3.60 (3H, s), 3.30 (2H, m), 2.30 (3H, s), 1.10 (3H,d).

EXAMPLE 38N-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)piperazine-1-sulfonamide

The subtitle product of step i) (2.0 g) was diluted inDCM/trifluoroacetic acid (10:1) for 1 h before concentrating in vacuoand purifying the crude product by reverse phase HPLC(acetonitrile/0.02M ammonium hydroxide (90% to 5% aqueous phase)) toyield the title compound as a white solid. Yield: 6 mg.

MS: APCI(+ve) 475 [M+H]⁺

¹H NMR δ_((DMSO)) 7.41 (1H, m), 7.31 (1H, m), 7.14 (1H, m), 5.87 (1H,s), 4.70 (1H, t), 4.38 (2H, s), 3.93 (1H, br. s), 3.44-3.26 (4H, m),2.81-2.67 (5H, m), 2.42 (1H, m), 1.05 (3H, d).

The intermediates for the above compound were prepared as follows:

i)piperazine-1-sulfonamide-4,6-dichloro-2-[(3-chloro-2-fluorobenzyl)thio]-pyrimidine

60% Sodium hydride (0.26 g) was added to a solution of the subtitleproduct of Example 31 step i) (3.11 g) in DMF (10 ml) at 0° C. Thereaction was removed from the cooling bath and stirred for 1 h beforeadding the subtitle product of Example 39 step ii) (5.0 g) as a solutionin DMF (5 ml). The reaction was stirred overnight before concentratingin vacuo. The residue was partitioned between H₂O (50 ml) and EtOAc (50ml) and the organics recovered, dried (MgSO₄) and concentrated in vacuo.The crude product was purified by flash column chromatography (20%, 25%then 30% EtOAc/isohexane) to yield the intermediate as a white solid.This material was diluted in (R)-alaninol (12 ml) and heated at 80° C.for 72 h. The residue was partitioned between H₂O (50 ml) and EtOAc (50ml) and the organics recovered, dried (MgSO₄) and concentrated in vacuoto afford the subtitle compound as a white solid. Yield: 2.0 g.

¹HNMR δ_((DMSO)) 7.15-6.93 (3H, m), 6.20 (1H, s), 5.00 (1H, d), 4.29(2H, s), 3.71 (1H, dd), 3.57 (1H, dd), 3.42 (4H, t), 3.20 (4H, t), 1.46(9H, s), 1.21 (3H, d).

EXAMPLE 39N-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)azetidine-1-sulfonamide

A solution of the subtitle product of step iii) (0.5 g) in (R)-alaninol(1.2 ml) was heated at 80° C. for 18 h before partitioning between EtOAcand H₂O. The organics were recovered, dried (MgSO₄) and concentrated.The residue was purified by column chromatography (1:90:109AcOH/EtOAc/iso-hexane) before treating the crude material withtrifluoroacetic acid (2 ml) and stirring for 12 min then quenching thereaction by the addition of 1M sodium hydroxide solution to pH>10.Saturated ammonium chloride solution was then added to pH 4 and theorganics recovered by extracting with EtOAc (3×20 ml). The organics weredried (MgSO₄) and concentrated in vacuo. The crude material was purifiedby reverse phase HPLC (95% to 20% 0.02M ammonium hydroxide/acetonitrile)to yield the title compound as a white solid. Yield: 90 mg.

MS APCI(+ve) 446 [M+H]⁺

¹H NMR δ_((CDCl3)) 7.24-7.21 (1H, m),7.08-6.97 (2H, m), 6.01 (1H, s),5.06-4.95 (1H, m), 4.35 (2H, s), 4.20-4.05 (1H, m), 3.98 (4H, t),3.74-3.70 (1H, m), 3.60-3.56 (1H, m), 2.23 (2H, quin.), 1.22 (3H, d).

The intermediates for this compound were prepared as follows:

i) 2-[(2,3-Difluorobenzyl)thio]pyrimidine-4,6-diol

A solution of potassium hydroxide (5.67 g) was added dropwise to asuspension of 2-mercaptopyrimidine-4,6-diol (14.56 g) in DMF (78 ml) andH₂O (39 ml) and the mixture stirred for 30 min. A solution of2,3-difluorobenzyl bromide (20.86 g) in THF (16 ml) was then addeddropwise and the mixture stirred for 18 h. The reaction was then cooledto 0° C. and the precipitate was filtered and washed with H₂O (4×100 ml)before drying in vacuo to afford the subtitle compound as a cream solid.Yield: 22.4 g.

¹H NMR δ_((DMSO)) 7.74 (1H, s), 7.39-7.32 (2H, m), 7.21-7.15 (1H, m),4.48 (2H, s).

ii) 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine

N,N-Dimethylaniline (10.3 ml) was added to a slurry of the the subtitleproduct of step i) (10.0 g) in phosphorus oxychloride (55 ml) and thesolution heated at reflux for 10 h. The reaction was allowed to cool andexcess phosphorus oxychloride was removed in vacuo before partitioningbetween Et₂O (110 ml) and H₂O (275 ml) and stirring for 1 h. The layerswere separated and the organics concentrated in vacuo to afford thecrude product. This crude product was purified by column chromatography(4% EtOAc/iso-hexane) to yield the subtitle compound as a white solid.Yield: 9.10 g.

¹H NMR δ_((DMSO)) 7.74 (1H, s), 7.39-7.32 (2H, m), 7.21-7.15 (1H, m)4.48 (2H, s).

iii)N-{6-Chloro-2-[(2,3-difluorobenzyl)thio]pyrimidin-4-yl}-N-{[2-(trimethylsilyl)ethoxy]methyl}azetidine-1-sulfonamide

To a solution of the product of Example 40 step i) (0.33 g) in dry DMF(4 ml) at 0° C. under nitrogen was added 60% sodium hydride (0.20 g).The reaction was allowed to warm outside the cooling bath for 15 minbefore recooling to 0° C. and addition of the product from step ii)(0.75 g) in DMF (2 ml) and the whole allowed to further stir at roomtemperature for 3 h. The reaction was quenched with2-(trimethylsilyl)ethoxymethyl chloride (0.86 ml) and allowed to stirfor 18 h before removal of the volatiles in vacuo and partitioning ofthe residue between EtOAc (100 ml) and H₂O (200 ml). The aqueous waswashed further with EtOAc (2×100 ml) and the organics combined, dried(MgSO₄) and concentrated in vacuo. The residue was purified by columnchromatography (1:22:177 AcOH/EtOAc/iso-hexane) to afford the subtitlecompound as a colourless oil. Yield: 0.65 g.

¹H NMR δ_((CDCl3)) 7.34-7.30 (1H, m), 7.19 (1H, s), 7.13-7.02 (2H, m),5.42 (2H, s), 4.45 (2H, s), 4.06 (4H, t), 3.65 (2H, t), 2.27 (2 h,quin.), 0.93 (2H, t), 0.00 (9H, s).

EXAMPLE 40N-(2-[(3-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)azetidine-1-sulfonamide

A solution of the subtitle product of step vi) (0.5 g) intrifluoroacetic acid (5 ml) was stirred for 15 min before the additionof 2M sodium hydroxide solution until pH>10. The aqueous was thenextracted with Et₂O (20 ml) before acidifying the aqueous to pH 4 with2M hydrochloric acid and extracting with EtOAc (2×20 ml). The EtOAcextracts were combined, dried (MgSO₄) and concentrated. The crudematerial was purified by reverse phase HPLC (90% to 5% 0.02M ammoniumhydroxide/acetonitrile) to yield the title compound as a white solid.Yield: 10 mg.

MS APCI(+ve) 462 [M+H]⁺

¹H NMR δ_((DMSO)) 7.59 (1H, t), 7.46 (1H, t), 7.15 (1H, t), 5.90 (1H,s), 4.69 (1H, t), 4.37 (2H, s), 3.95 (1H, br.s), 3.81 (4H, m), 3.44-3.21(2H, m), 2.12 (2H, m), 1.05 (3H, d).

The intermediates for this compound were prepared as follows:

i) Azetidine-1-sulfonamide

Azetidine (4.23 g) was added to a solution of sulfamide (7.48 g) in1,4-dioxan (120 ml) and heated at reflux for 24 h. The volatiles wereremoved under reduced pressure and the residue suspended in refluxingCHCl₃ (500 ml) for 10 min before decanting. The residue was againsuspended in hot CHCl₃ (500 ml) for 10 min before decanting. Thefiltrates were combined and concentrated in vacuo to afford the subtitleproduct as a white solid. Yield: 4.1 g.

¹H NMR δ_((DMSO)) 6.91 (2H, s), 3.74 (4H, t), 2.15 (2H, quin.).

ii)N-[2-(Benzylthio)-6-chloropyrimidin-4-yl]-N-{[2-(trimethylsilyl)ethoxy]methyl}-azetidine-1-sulfonamide

The subtitle compound was prepared as a yellow oil by the method ofExample 32 step i) by reacting the subtitle product of step i) (4.6 g)with the subtitle product of Example 19 step ii) (12.9). Yield: 12.9 g.

MS APCI(+ve) 537 [M+H]⁺

iii)N-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}azetidine-1-sulfonamide

The subtitle compound was prepared as a yellow oil by the method ofExample 32 step ii) by reacting the subtitle product of step ii) (12.2g) with (R)-alaninol (18 ml). Yield: 11.3 g.

MS APCI(+ve) 540 [M+H]⁺

iv)N-(2-(Benzylsulfonyl)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}azetidine-1-sulfonamide

m-Chloroperbenzoic acid was added as a single portion to a solution ofthe subtitle product of step iii) (11.3 g) in DCM (500 ml) and stirredfor 1 h. Saturated sodium thiosulfate solution (100 ml) was added andstirred vigourously until no peroxide was detected. The organics wereseparated and extracted with saturated sodium bicarbonate solution (200ml) and brine (50 ml), dried (MgSO₄) and concentrated to yield thesubtitle compound as a crude solid. Yield: 10.9 g.

MS APCI(+ve) 572 [M+H]⁺

v) Sodium4-((azetidin-1-ylsulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidine-2-thiolate

Sodium hydrosulfide hydrate (1.18 g) was added to a solution of thesubtitle product of step iv) (8.0 g) in DMSO (67 ml) and the greensolution stirred for 2 h. A farther aliquot of sodium hydrosulfidehydrate (0.79 g) was added and stirred for 1 h. This aliquot additionwas repeated twice more before heating the solution at 50° C. for 30min. The resulting reaction solution was used directly in the followingstep. The subtitle compound was also kept as a stock solution forfurther reaction with alkyl halides, described in Examples 41-42.

MS APCI(+ve) 450 [M+H]⁺

vi)N-(2-[(3-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}azetidine-1-sulfonamide

3-Chloro-2-fluorobenzyl bromide (3.13 g) was added to an aliquot of thereaction solution of step v) (18 ml) containing the subtitle product ofstep v) and the reaction stirred for 1 h. The reaction was partitionedbetween EtOAc (20 ml) and H₂O (20 ml) and the organics concentrated invacuo. The residue was purified by column chromatography (20% then 40%EtOAc/iso-hexane) to afford the subtitle compound as an oil which wasused directly in the subsequent step.

MS APCI(+ve) 592 [M+H]⁺

EXAMPLE 41N-{6-{[(1R)-2-Hydroxy-1-methylethyl]amino}-2-[(2,3,4-trifluorobenzyl)thio]-pyrimidin-4-yl}azetidine-1-sulfonamide

A solution of the subtitle product of step i) in trifluoroacetic acid (5ml) was stirred for 15 min before the addition of 2M sodium hydroxidesolution until pH>10. The aqueous was then extracted with Et₂O (20 ml)followed by EtOAc (2×20 ml). The EtOAc extracts were combined, dried(MgSO₄) and concentrated. The crude material was purified by reversephase HPLC (90% to 5% 0.02M ammonium hydroxide/acetonitrile) to yieldthe title compound as a white solid. Yield: 51 mg.

MS APCI(+ve) 464 [M+H]⁺

¹H NMR δ_((DMSO)) 10.50 (1H, br. s), 7.47 (1H, m), 7.25 (2H, m), 5.94(1H, m), 4.70 (1H, br. s), 4.36 (2H, s), 4.04 (1H, br. s), 3.86 (4H, m),3.40-3.25 (2H, m), 2.10 (2H, m), 1.05 (3H, d).

The intermediates for this compound were prepared as follows:

i)N-{6-{[(1R)-2-Hydroxy-1-methylethyl]amino}-2-[(2,3,4-trifluorobenzyl)thio]-pyrimidin-4-yl}-N-{[2-(trimethylsilyl)ethoxy]methyl}azetidine-1-sulfonamide

2,3,4-Trifluorobenzyl bromide (3.15 g) was added to an aliquot of thereaction solution of step v) (18 ml) containing the subtitle product ofstep v) and the reaction stirred for 1 h. The reaction was partitionedbetween EtOAc (20 ml) and H₂O (20 ml) and the organics concentrated invacuo. The residue was purified by column chromatography (20% then 40%EtOAc/iso-hexane) to afford the subtitle compound as an oil which wasused directly in the subsequent step.

MS APCI(+ve) 594 [M+H]⁺

EXAMPLE 42N-(2-[(2,3-Difluoro-4-methylbenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)azetidine-1-sulfonamide

A solution of the subtitle product of step i) in trifluoroacetic acid (5ml) was stirred for 15 min before the addition of 2M sodium hydroxidesolution until pH>10. The aqueous was then extracted with Et₂O (20 ml)followed by EtOAc (2×20 ml). The EtOAc extracts were combined, dried(MgSO₄) and concentrated. The crude material was purified by reversephase HPLC (90% to 5% 0.02M ammonium hydroxide/acetonitrile) to yieldthe title compound as a white solid. Yield: 42 mg.

MS APCI(+ve) 460 [M+H]⁺

¹H NMR δ_((DMSO)) 7.29 (1H, t), 7.02 (1H, t), 5.93 (1H, s), 4.70 (1H,t), 4.34 (2H, s), 4.05 (1H, br. s), 3.85 (4H, m), 3.41 (1H, m), 3.28(1H, m), 2.25 (3H, s), 2.10 (2H, quin.), 1.06 (3H, d).

The intermediates for this compound were prepared as follows:

i)N-(2-[(2,3-Difluoro-4-methylbenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}azetidine-1-sulfonamide

2,3-Difluoro-4-methylbenzyl bromide (3.10 g) was added to an aliquot ofthe reaction solution of step v) (18 ml) containing the subtitle productof step v) and the reaction stirred for 1 h. The reaction waspartitioned between EtOAc (20 ml) and H₂O (20 ml) and the organicsconcentrated in vacuo. The residue was purified by column chromatography(20% then 40% EtOAc/iso-hexane) to afford the subtitle compound as anoil which was used directly in the subsequent step.

MS APCI(+ve) 590 [M+H]⁺

EXAMPLE 43N-(2-[(2-Fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)methanesulfonamide

The title product was prepared from a solution of the product of stepiv) (4 ml) and quenching with 2-fluorobenzyl bromide (0.5 g) at roomtemperature. After 30 min the reaction mixture was partitioned betweenEtOAc (20 ml) and saturated brine (20 ml). The organic layer wascollected and the solvent evaporated to dryness. The residue was passedthrough a pad of silica gel (1:1 EtOAc/iso-hexane) to give theintermediate product as a gum. This was dissolved in acetonitrile (10ml) and treated with 1M hydrochloric acid with stirring at ambienttemperture over 24 h. The volatiles were removed in vacuo and theresidue purified by mass directed reverse phase HPLC to give the titlecompound as a white foam. Yield: 5 mg.

MS APCI(+ve) 387 [M+H]⁺

The intermediates for this compound were prepared as follows:

i)N-[2-(benzylthio)-6-chloropyrimidin-4-yl]-N-{[2-(trimethylsilyl)ethoxy]methyl}-methanesulfonamide

To a solution of methanesulfonamide (4.63 g) in dry DMF (60 ml) at 0° C.under nitrogen was added 60% sodium hydride (3.9 g) portionwise over 5min. After complete addition the ice bath was removed for 15 min andthen returned. A solution of the subtitle product of Example 19 step ii)in DMF (30 ml) was added dropwise over 5 min. After complete additionthe ice bath was removed and the whole stirred at ambient temperaturefor 3 h. The ice bath was returned before adddingtrimethylsilylethoxymethyl chloride (8.6 ml) to the reaction mixture.The reaction mixture was allowed to reach ambient temperature andfurther stirred for 24 h. The reaction mixture was partitioned betweenEtOAc and H₂O. The organic phase collected, dried (MgSO₄) and solventremoved in vacuo to leave the subtitle compound as a pale yellow oil.Yield: 21.2 g.

MS APCI(+ve) 460 [M+H]⁺

ii)N-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}methanesulfonamide

To a solution of the product of step i) (21.2 g) in NMP (40 ml) wasadded (R)-alaninol (10 g) and the whole heated at 80° C. for 4 h. Thereaction mixture was then partitioned between EtOAc and H₂O. The organicphase was collected, dried (MgSO₄) and the solvent removed to leave apale yellow oil. This was purified by silica gel chromatography (60:40iso-hexane EtOAc) to afford the subtitle compound as a colourless oil.Yield: 13.9 g.

MS APCI(+ve) 499 [M+H]⁺

iii)N-(2-(Benzylsulfonyl)-6{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}methanesulfonamide

To a solution of the product of step ii) (6.8 g) in DCM (300 ml) wasadded nm-chloroperbenzoic acid (8 g) at ambient temperature withstirring. After 6 h a concentrated solution of sodium thiosulphate (50ml) was added and the organic phase collected. The organic phase wasthen washed with saturated sodium bicarbonate solution (×2) followed bybrine. The organic phase was dried (MgSO₄) and the solvent evaporated toleave the subtitle compound as a colourless foam. Yield: 7.0 g.

MS APCI(+ve) 531 [M+H]⁺, MS APCI(−ve) 529 [M−H]⁺

iv) Sodium4-{[(1R)-2-hydroxy-1-methylethyl]amino}-6-((methylsulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino)pyrimidine-2-thiolate

To a solution of the product of step iii) (3.97 g) in DMSO (30 ml) wasadded sodium hydrosulphide hydrate (0.84 g). Stirring was continued fora further 2 h and additional aliquots of 0.42 g of sodium hydrosulphidewere added until complete disappearance of starting material as assessedby reverse phase HPLC-MS. The subtitle compound was also kept as a stocksolution for further reaction with alkyl halides described in examples43-53 and 137.

MS APCI(−ve) 407 [M−H]⁺

EXAMPLE 44N-(2-[(2,5-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)methanesulfonamide

The title compound was prepared from a solution of the product ofExample 43 step iv) (4 ml) and quenching with 2,5-difluorobenzyl bromide(0.5 g) using the method described for Example 43 to give the titlecompound as a white foam. Yield: 5 mg.

MS APCI(+ve) 405 [M+H]⁺, MS APCI(−ve) 403 [M−H]⁺

EXAMPLE 45N-(2-[(2,4-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)methanesulfonamide

The title compound was prepared from a solution of the product ofExample 43 step iv) (4 ml) and quenching with 2,4-difluorobenzyl bromide(0.5 g) using the method described for Example 43 to give the titlecompound as a white foam. Yield: 12 mg.

MS APCI(+ve) 405 [M+H]⁺, MS APCI(−ve) 403 [M−H]⁺

EXAMPLE 46N-(2-[(2,6-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)methanesulfonamide

The title compound was prepared from a solution of the product ofExample 43 step iv) (4 ml) and quenching with 2,6-difluorobenzyl bromide(0.5 g) using the method described for Example 43 to give the titlecompound as a white foam. Yield: 10 mg.

MS APCI(+ve) 405 [M+H]⁺, MS APCI(−ve) 403 [M−H]⁺

EXAMPLE 47N-(2-[(2,3,6-Trifluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)methanesulfonamide

The title compound was prepared from a solution of the product ofExample 43 step iv) (4 ml) and quenching with 2,3,6-trifluorobenzylbromide (0.5 g) using the method described for Example 43 to give thetitle compound as a white foam. Yield: 14 mg.

MS APCI(+ve) 423 [M+H]⁺, MS APCI(−ve) 421 [M−H]⁺

EXAMPLE 48N-(2-[(5-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)methanesulfonamide

The title compound was prepared from a solution of the product ofExample 43 step iv) (4 ml) and quenching with 5-chloro-2-fluorobenzylbromide (0.5 g) using the method described for Example 43 to give thetitle compound as a white foam. Yield: 8 mg.

MS APCI(+ve) 421 [M+H]⁺, MS APCI(−ve) 419 [M−H]⁺

EXAMPLE 49N-{6-{[(1R)-2-Hydroxy-1-methylethyl]amino}-2-[(2,4,5-trifluorobenzyl)thio]-pyrimidin-4-yl}methanesulfonamide

The title compound was prepared from a solution of the product ofExample 43 step iv) (4 ml) and quenching with 2,4,5-trifluorobenzylbromide (0.5 g) using the method described for Example 43 to give thetitle compound as a white foam. Yield: 7 mg.

MS APCI(+ve) 423 [M+H]⁺, MS APCI(−ve) 421 [M−H]⁺

EXAMPLE 50N-(2-[(3-Chloro-2,6-difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)methanesulfonamide

The title compound was prepared from a solution of the product ofExample 43 step iv) (4 ml) and quenching with3-chloro-2,6-difluorobenzyl bromide (0.5 g) using the method describedfor Example 43 to give the title compound as a white foam. Yield: 27 mg.

MS APCI(+ve) 439 [M+H]⁺

EXAMPLE 51N-{6-{[(1R)-2-Hydroxy-1-methylethyl]amino}-2-[(2,4,6-trifluorobenzyl)thio]-pyrimidin-4-yl}methanesulfonamide

The title compound was prepared from a solution of the product ofExample 43 step iv) (4 ml) and quenching with 2,4,6-trifluorobenzylbromide (0.5 g) using the method described for Example 43 to give thetitle compound as a white foam. Yield: 42 mg.

MS APCI(+ve) 423 [M+H]⁺

EXAMPLE 52N-(2-[(2-Chloro-3,6-difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)methanesulfonamide

The title compound was prepared from a solution of the product ofExample 43 step iv) (4 ml) and quenching with2-chloro-3,6-difluorobenzyl bromide (0.5 g) using the method describedfor Example 43 to give the title compound as a white foam. Yield: 40 mg.

MS APCI(+ve) 439 [M+H]⁺

EXAMPLE 53N-(2-[(2-Chloro-6-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)methanesulfonamide

The title compound was prepared from a solution of the product ofExample 43 step iv) (4 ml) and quenching with 2-chloro-6-fluorobenzylbromide (0.5 g) using the method described for Example 43 to give thetitle compound as a white foam. Yield: 32 mg.

MS APCI(+ve) 421 [M+H]⁺

General Procedure for the Synthesis of Examples 54 to 99.

To the required sulfonyl chloride (0.15 mM) was added a solution of thesubtitle product of Example 3 step ii) (0.05 mM) in pyridine (0.4 ml)and 4-N,N-dimethylaminopyridine (0.05 mM) in pyridine (0.2 ml) beforethe reaction mixture was stirred at room temperature for three days. 3MHydrochloric acid (0.2 ml) was added and stirring maintained for 18 hbefore the solvent was removed under reduced pressure. The residue wasdissolved in DMSO/H₂O (400 μl; 3:1), filtered through a PORVAIR filterand the product purified by mass directed reverse phase HPLC to affordthe title products of Examples 54 to 99.

EXAMPLE 54N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-4-methylbenzenesulfonamide

Yield: 7 mg.

MS: APCI (+ve) 369 [M+H]⁺

EXAMPLE 55N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-2,4,6-trimethylbenzenesulfonamide

Yield: 11 mg.

MS: APCI (+ve) 473[M+H]⁺

EXAMPLE 56N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}naphthalene-2-sulfonamide

Yield: 14 mg.

MS: APCI (+ve) 481 [M+H]⁺

EXAMPLE 57N-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-1-(R,S)-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanesulfonamide

Yield: 4 mg.

MS: APCI (+ve) 528 [M+H]⁺

EXAMPLE 58N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-4-bromobenzenesulfonamide

Yield: 7 mg.

MS: APCI (+ve) 509/511 [M+H]⁺

EXAMPLE 59N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide

Yield: 14 mg.

MS: APCI (+ve) 487 [M+H]⁺

EXAMPLE 60N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-2-bromobenzenesulfonamide

MS: APCI (+ve) 509/511 [M+H]⁺

EXAMPLE 61N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-4-(trifluoromethyl)benzenesulfonamide

Yield: 14 mg.

MS: APCI (+ve) 499 [M+H]⁺

EXAMPLE 62N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-3-(trifluoromethyl)benzenesulfonamide

Yield: 9 mg.

MS: APCI (+ve) 499 [M+H]⁺

EXAMPLE 63N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-2,5-dimethoxybenzenesulfonamide

Yield: 13 mg.

MS: APCI (+ve) 491 [M+H]⁺

EXAMPLE 64N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-2,1,3-benzoxadiazole-4-sulfonamide

Yield: 4 mg.

MS: APCI (+ve) 473 [M+H]⁺

EXAMPLE 65N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-5-isoxazol-3-ylthiophene-2-sulfonamide

Yield: 8 mg.

MS: APCI (+ve) 504 [M+H]⁺

EXAMPLE 66N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-2,6-dichlorobenzenesulfonamide

Yield: 10 mg.

MS: APCI (+ve) 499/501/503 [M+H]⁺

EXAMPLE 67N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-2,6-difluorobenzenesulfonamide

Yield: 7 mg.

MS: APCI (+ve) 467 [M+H]⁺

EXAMPLE 68N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-4-(1,1-dimethylpropyl)benzenesulfonamide

Yield: 13 mg.

MS: APCI (+ve) 501 [M+H]⁺

EXAMPLE 69N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-2-chloro-4-fluorobenzenesulfonamide

Yield: 9 mg.

MS: APCI (+ve) 483/485 [M+H]⁺

EXAMPLE 70N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-3-chloro-4-fluorobenzenesulfonamide

Yield: 15 mg.

MS: APCI (+ve) 483/485 [M+H]⁺

EXAMPLE 71N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-2,5-dichlorobenzenesulfonamide

Yield: 11 mg.

MS: APCI (+ve) 499/501/503 [M+H]⁺

EXAMPLE 72N-{2-(Benzylthio)-6[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-4-propylbenzenesulfonamide

Yield 14 mg.

MS: APCI (+ve) 473 [M+H]⁺

EXAMPLE 73N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-3-bromobenzenesulfonamide

Yield: 17 mg.

MS: APCI (+ve) 509/511 [M+H]⁺

EXAMPLE 74N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-3-chloro-2-methylbenzenesulfonamide

Yield: 13 mg.

MS: APCI (+ve) 479/481 [M+H]⁺

EXAMPLE 75N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-2,5-dichlorothiophene-3-sulfonamide

Yield: 6 mg.

MS: APCI (+ve) 505/507/509 [M+H]⁺

EXAMPLE 76N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-3,4-dimethoxybenzenesulfonamide

Yield: 11 mg.

MS: APCI (+ve) 491 [M+H]⁺

EXAMPLE 77N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-2,3-dichlorobenzenesulfonamide

Yield: 11 mg.

MS: APCI (+ve) 499/501/503 [M+H]⁺

EXAMPLE 78N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-5-chlorothiophene-2-sulfonamide

Yield: 8 mg.

MS: APCI (+ve) 471/473 [M+H]⁺

EXAMPLE 79N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-2-chloro-6-methylbenzenesulfonamide

Yield: 7 mg.

MS: APCI (+ve) 479/481 [M+H]⁺

EXAMPLE 80N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-3,4-dichlorobenzenesulfonamide

Yield: 13 mg.

MS: APCI (+ve) 499/501/503 [M+H]⁺

EXAMPLE 81N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-3,5-dichlorobenzenesulfonamide

Yield: 14 mg.

MS: APCI (+ve) 499/501/503 [M+H]⁺

EXAMPLE 82N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-2,4-dichloro-5-methylbenzenesulfonamide

Yield: 12 mg.

MS: APCI (+ve) 513/515/517 [M+H]⁺

EXAMPLE 83N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-3,4-difluorobenzenesulfonamide

Yield: 15 mg.

MS: APCI (+ve) 467 [M+H]⁺

EXAMPLE 84N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-2-methylbenzenesulfonamide

Yield: 14 mg.

MS: APCI (+ve) 445 [M+H]⁺

EXAMPLE 85N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-O-methylethyl)amino]pyrimidin-4-yl}-3-methoxybenzenesulfonamide

Yield: 16 mg.

MS: APCI (+ve) 461 [M+H]⁺

EXAMPLE 86N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-2,5-difluorobenzenesulfonamide

Yield: 12 mg.

MS: APCI (+ve) 467 [M+H]⁺

EXAMPLE 87N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-4-chloro-2,5-dimethoxybenzenesulfonamide

Yield: 9 mg.

MS: APCI (+ve) 525/527 [M+H]⁺

EXAMPLE 88N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}thiophene-3-sulfonamide

Yield: 18 mg.

MS: APCI (+ve) 437 [M+H]⁺

EXAMPLE 894-Acetyl-N-{2-(benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}benzenesulfonamide

Yield: 6 mg.

MS: APCI (+ve) 473 [M+H]⁺

EXAMPLE 90N-{2-(Benzylthio)-6[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-2-chloro-4,5-difluorobenzenesulfonamide

Yield: 5 mg.

MS: APCI (+ve) 501/503 [M+H]⁺

EXAMPLE 91N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-5-chloro-2,4-difluorobenzenesulfonamide

Yield: 4 mg.

MS: APCI (+ve) 501/503 [M+H]⁺

EXAMPLE 92N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}chloro-2,5-difluorobenzenesulfonamide

Yield: 9 mg.

MS: APCI (+ve) 501/503 [M+H]⁺

EXAMPLE 93N-{2-(Benzylthio)-6[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}biphenyl-4-sulfonamide

Yield: 14 mg.

MS: APCI (+ve) 507 [M+H]⁺

EXAMPLE 94N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-2-methoxy-4-methylbenzenesulfonamide

Yield: 10 mg.

MS: APCI (+ve) 475 [M+H]⁺

EXAMPLE 95N-{2-(Benzylthio)-6[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-3-chloro-4-methylbenzenesulfonamide

Yield: 14 mg.

MS: APCI (+ve) 479/481 [M+H]⁺

EXAMPLE 96N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-4-bromo-2-methylbenzenesulfonamide

Yield: 5 mg.

MS: APCI (+ve) 523/525 [M+H]⁺

EXAMPLE 97N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-4-phenoxybenzenesulfonamide

Yield: 7 mg.

MS: APCI (+ve) 523 [M+H]⁺

EXAMPLE 98N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-4-chloro-2,5-dimethylbenzenesulfonamide

Yield: 14 mg.

MS: APCI (+ve) 493/495 [M+H]⁺

EXAMPLE 99N-{2-(Benzylthio)-6-[((1R)-2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-2,3,4-trifluorobenzenesulfonamide

Yield: 5 mg.

MS: APCI (+ve) 485 [M+H]⁺

General Procedure for the Synthesis of Examples 100 to 105.

To the required sulfonyl chloride (0.15 mM) was added a solution of thesubtitle product of Example 3 step ii) (0.05 mM) in pyridine (0.4 ml)and 4-N,N-dimethylaminopyridine (0.05 mM) in pyridine (0.2 ml) beforethe reaction mixture was stirred at room temperature for three days. 3MHydrochloric acid (0.2 ml) was added and stirring maintained for 18 hbefore the solvent was removed under reduced pressure. The residue wasdissolved in DMSO/H₂O (400 μl; 3:1) and filtered through a PORVAIRfilter before the product was purified by mass directed reverse phaseHPLC to afford the title products of Examples 100 to 105 as solutionsamples.

EXAMPLE 100N-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-4-methoxybenzenesulfonamide

MS: APCI (+ve) 461 [M+H]⁺

EXAMPLE 101N-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-2,4-dichlorobenzenesulfonamide

MS: APCI (+ve) 499 [M+H]⁺

EXAMPLE 102N-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)thiophene-2-sulfonamide

MS: APCI (+ve) 437 [M+H]⁺

EXAMPLE 103N-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-2,5-dimethylbenzenesulfonamide

MS: APCI (+ve) 459 [M+H]⁺

EXAMPLE 104N-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-1,2-dimethyl-1H-imidazole-4-sulfonamide

MS: APCI (+ve) 449 [M+H]⁺

EXAMPLE 105N-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)butane-1-sulfonamide

MS: APCI (+ve) 411 [M+H]⁺

EXAMPLE 106N-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)morpholine-4-sulfonamide

2,3-Difluorobenzyl bromide (0.95 g) was added to an aliquot of thereaction solution of step iv) (2 ml) containing the subtitle product ofstep iv) and the reaction stirred for 2 h. The reaction was partitionedbetween EtOAc (20 ml) and brine (20 ml). The aqueous was extracted withEtOAc (2×20 ml) and the organics concentrated in vacuo. The residue waspurified by column chromatography (30% then 40% EtOAc/iso-hexane) toafford the subtitle product as an oil that was diluted in acetonitrile(5 ml) and 2M hydrochloric acid (5 ml) and was stirred overnight beforeremoval of the volatiles in vacuo. The crude material was purified byreverse phase BPLC (gradient 95% to 20% 0.02M ammoniumhydroxide/acetonitrile) to yield the title compound as a white solid.Yield: 0.17 g.

MS APCI(+ve) 476 [M+H]⁺

¹H NMR δ_((DMSO)) 10.57 (1H, bs), 7.40 (1H, bt), 7.32 (2H, m), 7.15 (1H,m), 5.90 (1H, s), 4.71 (1H, bs), 4.39 (2H, t), 4.02 (1H, bs), 3.60 (4H,t), 3.40 (1H, m), 3.30 (1H, m), 3.18 (4H, bs), 1.06 (3H, d).

The intermediates for this compound were prepared as follows:

i)N-{6-Chloro-2-[benzylthio]pyrimidin-4-yl}-N-{[2-(trimethylsilyl)-ethoxy]methyl}morpholine-4-sulfonamide

The subtitle compound was prepared as an oil by the method of Example 32step i) (8.9 g) using the subtitle product of Example 19 step ii) andthe subtitle product of Example 36 step i) (4.7 g) and2-(trimethylsilyl)ethoxymethyl chloride (6.1 g). Yield: 11.8 g.

MS APCI(+ve) 401 [M+H]⁺

ii)N-(2-[benzylthio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}morpholine-4-sulfonamide

The subtitle compound was prepared as a yellow oil by the method ofExample 43 step ii) by reacting the subtitle product of step i) (11.75g) with (R)-alaninol (3.4 ml) in NMP (30 ml). Yield: 12.2 g.

MS APCI(+ve) 570 [M+H]⁺

iii)N-(2-[benzylsulfonyl]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}morpholine-4-sulfonamide

m-Chloroperbenzoic acid (5.87 g) was added as a single portion to asolution of the subtitle product of step iii) (5.83 g) in DCM (220 ml)and stirred for 2.5 h. A further aliquot of m-chloroperbenzoic acid (1.0g) was added and stirring maintained for 1 h. Saturated sodiumthiosulfate solution (100 ml) was added and stirred vigourously until noperoxides were detected. The organics were separated and extracted withsaturated sodium bicarbonate solution (200 ml) and brine (50 ml), dried(MgSO₄) and concentrated to yield the subtitle compound as a crude beigewhite solid. Yield: 5.6 g.

MS APCI(+ve) 602 [M+H]⁺

iv) Sodium4-{[(1R)-2-hydroxy-1-methylethyl]amino}-6-((morpholin-4-ylsulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino)pyrimidine-2-thiolate

Sodium hydrosulfide hydrate (0.62 g) was added to a solution of thesubtitle product of step iii) (2.5 g) in DMSO (5 ml) and the greensolution stirred for 1.25 h. A further aliquot of sodium hydrosulfidehydrate (0.28 g) was added and stirred for 45 min. A further aliquot ofsodium hydrosulfide hydrate (0.32 g) was added and stirred for 1.25 hbefore the addition of a final aliquot of sodium hydrosulfide hydrate(0.10 g) in DMSO (1 ml). The resulting reaction solution was dilutedwith DMSO (10 ml) and used directly in the following step. The subtitlecompound was also kept as a stock solution for further reaction withalkyl halides, described in Examples 107-110.

MS APCI(+ve) 480 [M+H]⁺

EXAMPLE 107N-{6-{[(1R)-2-Hydroxy-1-methylethyl]amino}-2-[(2,3,4-trifluorobenzyl)thio]-pyrimidin-4-yl}morpholine-4-sulfonamide

2,3,4-Trifluorobenzyl bromide (1.04 g) was added to an aliquot of thereaction solution of Example 106 step iv) (2 ml) containing the subtitleproduct of Example 106 step iv) and the reaction stirred for 2 h. Thereaction was partitioned between EtOAc (20 ml) and brine (20 ml). Theaqueous was extracted with EtOAc (2×20 ml) and the organics concentratedin vacuo. The residue was purified by column chromatography (50% then60% EtOAc/iso-hexane) to afford the subtitle product as an oil that wasdiluted in acetonitrile (5 ml) and 2M hydrochloric acid (5 ml) and wasstirred overnight before removal of the volatiles in vacuo. The crudematerial was purified by reverse phase HPLC (gradient 95% to 20% 0.02Mammonium hydroxide/acetonitrile) to yield the title compound as a whitesolid. Yield: 0.14 g.

MS APCI(+ve) 494 [M+H]⁺

¹H NMR δ_((DMSO)) 10.57 (1H, bs), 7.45 (1H, bs), 7.25 (2H, m), 5.90 (1H,s), 4.71 (1H, bs), 4.36 (2H, s), 4.02 (1H, s), 3.60 (4H, bs), 3.38 (1H,m), 3.30 (1H, m), 3.15 (4H, bs), 1.07 (3H, d).

EXAMPLE 108N-{6-{[(1R)-2-Hydroxy-1-methylethyl]amino}-2-[(2,3,5-trifluorobenzyl)thio]-pyrimidin-4-yl}morpholine-4-sulfonamide

2,3,5-Trifluorobenzyl bromide (1.04 g) was added to an aliquot of thereaction solution of Example 106 step iv) (2 ml) containing the subtitleproduct of Example 106 step iv) and the reaction stirred for 2 h. Thereaction was partitioned between EtOAc (20 ml) and brine (20 ml). Theaqueous was extracted with EtOAc (2×20 ml) and the organics concentratedin vacuo. The residue was purified by column chromatography (50% then60% EtOAc/iso-hexane) to afford the subtitle product as an oil that wasdiluted in acetonitrile (5 ml) and 2M hydrochloric acid (5 ml) and wasstirred overnight before removal of the volatiles in vacuo. The crudematerial was purified by reverse phase HPLC (gradient 95% to 20% 0.02Mammonium hydroxide/acetonitrile) to yield the title compound as a whitesolid. Yield: 0.16 g.

MS APCI(−ve) 492 [M−H]⁻

¹H NMR δ_((DMSO)) 10.61 (1H, bs), 7.38 (3H, bm), 5.91 (1H, s), 4.71 (1H,bs), 4.36 (2H, t), 4.02 (1H, bs), 3.59 (4H, bs), 3.37 (1H, m), 3.30 (1H,m), 3.14 (4H, bs), 1.05 (3H, d).

EXAMPLE 109N-(2-[(2,3-Difluoro-4-methylbenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)morpholine-4-sulfonamide

2,3,-Difluoro-4-methylbenzyl bromide (1.02 g) was added to an aliquot ofthe reaction solution of Example 106 step iv) (2 ml) containing thesubtitle product of Example 106 step v) and the reaction stirred for 2h. The reaction was partitioned between EtOAc (20 ml) and brine (20 ml).The aqueous was extracted with EtOAc (2×20 ml) and the organicsconcentrated in vacuo. The residue was purified by column chromatography(70% EtOAc/iso-hexane) to afford the subtitle product as an oil that wasdiluted in acetonitrile (5 ml) and 2M hydrochloric acid (5 ml) and wasstirred overnight before removal of the volatiles in vacuo. The crudematerial was purified by reverse phase HPLC (gradient 95% to 20% 0.02Mammonium hydroxide/acetonitrile) to yield the title compound as a whitesolid. Yield: 0.12 g.

MS APCI(−ve) 488 [M−H]⁻

¹H NMR δ_((DMSO)) 10.57 (1H, bs), 7.28 (2H, bs), 7.02 (1H, t), 5.90 (1H,bs), 4.71 (1H, bs), 4.34 (2H, bm), 4.03 (1H, bs), 3.59 (4H, bs), 3.39(1H, m), 3.30 (1H, m), 3.15 (4H, bs), 2.24 (3H, s), 1.07 (3H, d).

EXAMPLE 110N-(2-[(4-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)morpholine-4-sulfonamide

4-Chloro-2-fluorobenzyl bromide (1.03 g) was added to an aliquot of thereaction solution of Example 106 step iv) (2 ml) containing the subtitleproduct of Example 106 step iv) and the reaction stirred for 2 h. Thereaction was partitioned between EtOAc (20 ml) and brine (20 ml). Theaqueous was extracted with EtOAc (2×20 ml) and the organics concentratedin vacuo. The residue was purified by column chromatography (66%EtOAc/iso-hexane) to afford the subtitle product as an oil that wasdiluted in acetonitrile (5 ml) and 2M hydrochloric acid (5 ml) and wasstirred overnight before removal of the volatiles in vacuo. The crudematerial was purified by reverse phase HPLC (gradient 95% to 20% 0.02Mammonium hydroxide/acetonitrile) to yield the title compound as a whitesolid. Yield: 90 mg.

MS APCI(−ve) 490 [M−H]⁻

¹H NMR δ_((DMSO)) 10.56 (1H, bs), 7.63 (1H, bt), 7.42 (1H, d), 7.31 (1H,bs), 7.23 (1H, d), 5.90 (1H, s), 4.72 (1H, bs), 4.32 (2H, bs), 4.30 (1H,bs), 3.59 (4H, bs), 3.40 (1H, m), 3.30 (1H, m), 3.15 (4H, bs), 1.06 (3H,d).

EXAMPLE 111N-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)pyrrolidine-1-sulfonamide

2,3-Difluorobenzyl bromide (2.65 g) was added to an aliquot of thereaction solution of step v) (12.6 ml) containing the subtitle productof step v) and the reaction stirred for 1 h. The reaction waspartitioned between EtOAc (20 ml) and H₂O (20 ml), the organics wererecovered, dried (MgSO₄) and concentrated in vacuo. The residue waspurified by column chromatography (650:350:1 iso-hexane/EtOAc/AcOH) toafford the subtitle compound as an oil that was diluted intrifluoroacetic acid (2 ml) and was stirred for 12 min before quenchingthe reaction by the addition of 1M sodium hydroxide solution to pH>10.The aqueous was washed with Et₂O before saturated ammonium chloridesolution was added to acidify the aqueous to pH 4 followed by extractingwith EtOAc (3×20 ml). The EtOAc extracts were combined, dried (MgSO₄)and concentrated in vacuo. The crude material was purified by reversephase HPLC (gradient 95% to 20% 0.02M ammonium hydroxide/acetonitrile)to yield the title compound as a white solid. Yield: 0.52 g. MSAPCI(+ve) 460 [M+H]+

¹H NMR δ_((CDCl3)) 7.25-7.20 (1H, m), 7.08-6.97 (2H, m), 5.95 (1H, s),4.98 (1H, d), 4.34 (2H, s), 4.15-4.01 (1H, m), 3.73-3.69 (1H, m),3.60-3.55 (1H, m), 3.39 (4H, t), 1.93-1.90 (4H, m), 1.21 (3H, d).

The intermediates for this compound were prepared as follows:

i) Pyrrolidine-1-sulfonamide

Pyrrolidine (3.37 g) and sulfamide (7.10 g) in 1,4-dioxane (110 ml) wereheated at reflux for 24 h. The solvent was evaporated under reducedpressure and the resulting solid suspended in CHCl₃. The suspension wasfiltered and the filtrate concentrated in vacuo to afford the subtitlecompound as a white solid. Yield: 5.35 g.

¹H NMR δ_((CDCl3)) 4.46 (2H, s), 3.31 (4H, t), 1.96-1.92 (4H, m).

ii)N-[2-(Benzylthio)-6-chloropyrimidin-4-yl]-N-{[2-(trimethylsilyl)ethoxy]methyl}-pyrrolidine-1-sulfonamide

To a solution of the product of step i) (5.0 g) in dry DMF (60 ml) at 0°C. under nitrogen was added 60% sodium hydride (2.66 g). The reactionwas allowed to warm outside the cooling bath for 15 min before recoolingto 0° C. and addition of the product from Example 19 step ii) (9.03 g)in DMF (20 ml) and the whole allowed to further stir at room temperaturefor 3 h. The reaction was quenched with 2-(trimethylsilyl)ethoxymethylchloride (6.50 ml) and allowed to stir for 18 h before removal of thevolatiles in vacuo and partitioning of the residue between EtOAc (100ml) and H₂O (200 ml). The aqueous was washed further with EtOAc (2×100ml) and the organics combined, dried (MgSO₄) and concentrated in vacuo.The residue was purified by column chromatography (1:18:181AcOH/EtOAc/iso-hexane) to afford the subtitle compound as a colourlessoil. Yield: 8.26 g.

MS APCI(+ve) 515 [M+H]⁺

iii)N-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolidine-1-sulfonamide

The subtitle compound was prepared as a yellow oil by the method ofExample 43 step ii) by reacting the subtitle product of step ii) (8.26g) with (R)-alaninol (3.61 g) in NMP (60 ml). Yield: 7.6 g.

MS APCI(+ve) 554 [M+H]⁺

iv)N-(2-Benzylsulfonyl)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolidine-1-sulfonamide

m-Chloroperbenzoic acid (11.07 g) was added as a single portion to asolution of the subtitle product of step iii) (9.41 g) in DCM (44 ml)and stirred for 6 h. Saturated sodium thiosulfate solution (100 ml) wasadded and stirred vigourously until no peroxides were detected. Theorganics were separated and extracted with saturated sodium bicarbonatesolution (200 ml) and brine (50 ml), dried (MgSO₄) and concentrated toyield the subtitle compound as a colourless foam. Yield: 1.0 g.

MS APCI(+ve) 531 [M+H]⁺

v) Sodium4-{[(1R)-2-hydroxy-1-methylethyl]amino}-6-((pyrrolidin-1-ylsulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino)pyrimidine-2-thiolate

Sodium hydrosulfide hydrate (2.15 g) was added to a solution of thesubtitle product of step iii) (4.5 g) in DMSO (37.8 ml) and the greensolution stirred for 1 h. A further aliquot of sodium hydrosulfidehydrate (0.1 g) was added and stirred for 1 h. A further aliquot ofsodium hydrosulfide hydrate (0.1 g) was added and stirred for 2 h beforethe addition of a final aliquot of sodium hydrosulfide hydrate (0.05 g).The resulting reaction solution was used directly in the following step.The subtitle compound was also kept as a stock solution for furtherreaction with alkyl halides, described in Examples 112-113.

MS APCI(+ve) 351 [M+H]⁺

EXAMPLE 112N-{6-{[(1R)-2-Hydroxy-1-methylethyl]amino}-2-[(2,3,4-trifluorobenzyl)thio]-pyrimidin-4-yl}pyrrolidine-1-sulfonamide

The title compound was prepared as a white solid by the method ofExample 111 using the subtitle product of Example 111 step v) (12.6 ml)and 2,3,4-trifluorobenzyl bromide (2.88 g). Yield: 0.12 g.

MS APCI(+ve) 478 [M+H]⁺

¹H NMR δ_((CDCl3)) 7.22-7.16 (1H, m), 7.01-6.86 (2H, m), 5.95 (1H, s),5.01 (1H, d), 4.30 (2H, s), 4.07 (1H, m), 3.74-3.70 (1H, m), 3.60-3.56(1H, m), 3.39 (4H, t), 1.94-1.90 (4H, m), 1.23 (3H, d).

EXAMPLE 113N-(2-[(2,3-Difluoro-4-methylbenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)pyrrolidine-1-sulfonamide

The title compound was prepared as a white solid by the method ofExample 111 using the subtitle product of Example 111 step v) (12.6 ml)and 2,3-difluoro-4-methylbenzyl bromide (2.83 g). Yield: 40 mg.

MS APCI(−ve) 372 [M−H]⁻

¹H NMR δ_((DMSO)) 10.36 (1H, s), 7.27 (1H, t), 7.01 (1H, t), 5.78 (1H,s), 4.69 (1H, t), 4.32 (2H, s), 4.03-3.87 (1H, m), 3.33-3.29 (1H, m),3.28-3.22 (4H, m), 2.24 (3H, s), 1.78-1.75 (4H, m), 1.06 (3H, d).

EXAMPLE 114N-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)piperidine-1-sulfonamide

The subtitle product of step ii) was heated in (R)-alaninol (2 ml) for 8days at 80° C. before partitioning between EtOAc (50 ml) and H₂O (50ml). The organics were recovered, dried (MgSO₄) and concentrated invacuo. The residue was purified by column chromatography (550:450:1EtOAc/iso-hexane/AcOH) to afford the title compound as a white solid.Yield: 106 mg.

MS APCI(+ve) 474 [M+H]⁺

¹H NMR δ_((CDCL3)) 7.24-7.20 (1H, m), 7.08-6.98 (2H, m), 6.02 (1H, s),4.36 (2H, s), 4.18-3.96 (1H, m), 3.74-3.70 (1H, m), 3.61-3.57 (1H, m),3.26 (4H, t), 1.65-1.59 (4H, m), 1.57-1.51 (2H, m), 1.22 (3H, d).

The intermediates for this compound were prepared as follows:

i) Piperidine-1-sulfonamide

Piperidine (3.0 g) and sulfamide (5.93 g) in 1,4-dioxane (100 ml) wereheated at reflux for 24 h. The solvent was evaporated under reducedpressure and the resulting solid suspended in CHCl₃. The suspension wasfiltered and the filtrate concentrated in vacuo to afford the subtitlecompound as a white solid. Yield: 3.85 g.

¹H NMR δ_((DMSO)) 6.65 (2H, s), 2.92 (4H, t), 1.59-1.53 (4H, m),1.45-1.40 (2H, m).

ii)N-{3-Chloro-5-[(2,3-difluorobenzyl)thio]phenyl}piperidine-1-sulfonamide

60% Sodium hydride (0.20 g) was added to a solution of the subtitleproduct of step i) (0.4 g) in DMF (6.7 ml) at 0° C. The reaction wasallowed to warm outside the cooling bath for 15 min before recooling to0° C. for 15 min. A solution of the subtitle product of Example 39 stepii) (0.75 g) in DMF (2 ml) was then added and stirring maintained for 3h. The reaction mixture was neutralised with methanolic hydrogenchloride before concentrating in vacuo. The residue was partitionedbetween EtOAc (100 ml) and H₂O (200 ml) and the organics recovered,dried (MgSO₄) and concentrated in vacuo. The residue was purified bycolumn chromatography (1:20:79 AcOH/EtOAc/iso-hexane) to afford thesubtitle compound as a colourless oil. Yield: 1.3 g.

MS APCI(+ve) 435 [M+H]⁺

EXAMPLE 115N-(2-[(2-Fluoro-3-methylbenzyl)thio]-6{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)methanesulfonamide

A solution of the subtitle product of step iii) (1.0 g) in (R)-alaninol(1.5 ml) was heated at 80° C. for 18 h before partitioning between EtOAcand H₂O. The organics were recovered, dried (MgSO₄) and concentrated.The residue was purified by column chromatography (1:76:133AcOH/EtOAc/iso-hexane) before diluting the crude material intrifluoroacetic acid (2 ml) and stirring for 12 min before quenching thereaction by the addition of 1M sodium hydroxide solution to pH>10. Theaqueous was extracted with Et₂O before being acidified with saturatedammonium chloride solution to pH 4 and extracting with EtOAc (3×20 ml).The EtOAc extracts were dried (MgSO₄) and concentrated in vacuo. Thecrude material was purified by reverse phase HPLC (gradient 95% to 20%0.02M ammonium hydroxide/acetonitrile) to yield the title compound as awhite solid. Yield: 0.33 g.

MS APCI(+ve) 401 [M+H]⁺

¹H NM δ_((DMSO)) 10.53 (1H, s), 7.36 (1H, t), 7.17 (1H, t), 7.01 (1H,t), 5.77 (1H, s), 4.70 (1H, s), 4.33 (2H, s), 4.01 (1H, s), 3.42-3.37(1H, m), 3.32 (3H, s), 3.31-3.26 (1H, m), 2.23 (3H, s), 1.07 (3H, d).

The intermediates for this compound were prepared as follows:

i) 2-[(2-Fluoro-3-methylbenzyl)thio]pyrimidine-4,6-diol

The subtitle compound was prepared as a yellow solid by the method ofExample 39 step i) using 2-fluoro-3-methylbenzyl bromide (7.0 g),2-mercaptopyrimidine-4,6-diol (5.0 g) and potassium hydroxide (1.93 g).Yield: 8.36 g.

MS APCI(+ve) 267 [M+H]⁺

ii) 4,6-Dichloro-2-[(2-fluoro-3-methylbenzyl)thio]pyrimidine

The subtitle compound was prepared as white crystals by the method ofExample 39 step ii) using the subtitle product of step i) (8.36 g),phosphorus oxychloride (47 ml) and N,N-dimethylaniline (8.9 ml). Yield:7.32 g.

¹H NMR δ_((CDCL3)) 7.32 (1H, t), 7.10 (1H, t), 7.03 (1H, s), 6.96 (1H,t), 4.40 (2H, s), 2.28 (3H, s).

iii)N-{6Chloro-2-[(2-fluoro-3-methylbenzyl)thio]pyrimidin-4-yl}-N-{[2-(trimethylsilyl)ethoxy]methyl}azetidine-1-sulfonamide

The subtitle compound was prepared as a colourless oil by the method ofExample 39 step iii) using the subtitle product of step ii) (2.45 g),methanesulfonamide (0.76 g), 60% sodium hydride (0.64 g) and2-(trimethylsilyl)ethoxymethyl chloride (1.42 ml). Yield: 3.14 g.

MS APCI(+ve) 434 [M+H]⁺

EXAMPLE 116N-{2-[(2-Fluoro-3-methylbenzyl)thio]-6-[(2-hydroxy-1,1-dimethylethyl)amino]-pyrimidin-4-yl}methanesulfonamide

The title compound was prepared as a white solid by the method ofExample 115 using the subtitle product of Example 115 step iii) (1.0 g),2-amino-2-methyl-1-propanol (1.5 ml) and trifluoroacetic acid (2 ml).Yield: 0.19 g.

MS APCI(+ve) 415 [M+H]⁺

¹H NMR δ_((CDCL3)) 7.25 (1H, t), 7.08 (1H, t), 6.97 (1H, t), 5.95 (1H,s), 4.94 (1H, s), 4.34 (2H, s), 3.64 (2H, s), 3.16 (3H, s), 2.28 (3H,s), 1.36 (6H, s).

EXAMPLE 117N-(2-[(2-Fluoro-3-methylbenzyl)thio]-6{[(1R)-1-(hydroxymethyl)propyl]amino}-pyrimidin-4-yl)methanesulfonamide

The title compound was prepared as a white solid by the method ofExample 115 using the subtitle product of Example 115 step iii) (1.0 g),(R)-(−)-2-amino-1-butanol (1.5 ml) and trifluoroacetic acid (2 ml).Yield: 0.19 g.

MS APCI(+ve) 415 [M+H]⁺

¹H NMR δ_((DMSO)) 10.52 (1H, s), 7.36 (1H, t), 7.17 (1H, t), 7.01 (1H,t), 5.81 (1H, s), 4.65 (1H, s), 4.32 (2H, s), 3.92 (1H, s), 3.42-3.37(1H, m), 3.31 (3H, s), 3.34-3.29 (1H, m), 2.23 (3H, s), 1.65-1.56 (1H,m), 1.41-1.32 (1H, m), 0.84 (3H, t).

EXAMPLE 118N-(2-{[2-Fluoro-3-(trifluoromethyl)benzyl]thio}-6{[(1R)-2-hydroxy-1-methylethyl]-amino}pyrimidin-4-yl)methanesulfonamide

The title compound was prepared as pale yellow crystals by the method ofExample 115 using the subtitle product of step iii) (0.21 g) and(R)-alaninol (0.3 ml). Yield: 0.12 g.

MS APCI(+ve) 455 [M+H]⁺

¹H NMR δ_((CDCl3)) 7.71 (1H, t), 7.49 (1H, t), 7.19 (1H, t), 5.95 (1H,s), 5.07 (1H, s), 4.35 (2H, s), 3.74-3.69 (1H, m), 3.59-3.54 (1H, m),3.15 (3H, s), 1.20 (3H, d).

The intermediates for this compound were prepared as follows:

i) 2-{[2-Fluoro-3-(trifluoromethyl)benzyl]thio}pyrimidine-4,6-diol

The subtitle compound was prepared as a yellow solid by the method ofExample 39 step i) using 2-fluoro-3-(trifluroromethyl)benzyl bromide(2.0 g), 2-mercaptopyrimidine-4,6-diol (1.12 g) and potassium hydroxide(0.44 g). Yield: 2.23 g.

MS APCI(+ve) 321 [M+H]⁺

ii) 4,6-Dichloro-2-[(2-fluoro-(3-trifluoromethyl)benzyl)thio]pyrimidine

The subtitle compound was prepared as white crystals by the method ofExample 39 step ii) using the subtitle product of step i) (2.23 g),phosphorus oxychloride (10.4 ml) and N,N-dimethylaniline (2.0 ml).Yield: 1.7 g.

¹H NMR δ_((CDCl3)) 7.75 (1H, t), 7.52 (1H, t), 7.18 (1H, t), 7.06 (1H,s), 4.43 (2H, s).

iii)N-(6-Chloro-2-{[2-fluoro-3-(trifluoromethyl)benzyl]thio}pyrimidin-4-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}methanesulfonamide

The subtitle compound was prepared as a colourless oil by the method ofExample 39 step iii) using the subtitle product of step ii) (0.57 g),methanesulfonamide (0.15 g), 60% sodium hydride (0.26 g) and2-(trimethylsilyl)ethoxymethyl chloride (0.3 ml). Yield: 0.21 g.

¹H NMR δ_((CDCl3)) 7.77 (1H, t), 7.53 (1H, t), 7.19 (1H, t), 7.12 (1H,s), 5.32 (2H, s), 4.45 (2H, s), 3.66 (2H, t), 3.32 (3H, s), 0.93 (2H,t), 0.00 (9H, s).

EXAMPLE 119N-(2-[(2,3-Difluoro-4-methylbenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)methanesulfonamide

The title compound was prepared from a solution of the product ofExample 43 step iv) (4 ml) and quenching 2,3-difluoromethylbenzylbromide (1.46 g) using the method descibed for Example 43 to give thetitle compound as a white solid. Yield: 4 mg.

MS APCI(+ve) 419 [+H]⁺

¹H NMR δ_((CD3OD)) 7.27-7.23 (1H, m), 6.93-6.89 (1H, m), 5.56 (1H, s),4.41 (2H, s), 3.91-3.81 (1H, m), 3.55-3.50 (1H, m), 3.48-3.43 (1H, m),3.03 (3H, s), 2.25 (3H, s), 1.16 (3H, d).

EXAMPLE 120N-(2-[(2-Fluoro-3-methoxybenzyl)thio]-6{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)methanesulfonamide

The title compound was prepared as a white foam by the method of Example40 using the subtitle product of step vii) (0.24 g) and trifluoroaceticacid (11.0 ml). Yield: 0.11 g.

MS APCI(+ve) 417 [M+H]⁺

¹H NMR δ_((DMSO)) 7.24 (1H, bs), 7.06 (3H, m), 5.77 (1H, s), 4.70 (1H,bt), 4.33 (2H, t), 4.00 (1H, bs), 3.82 (3H, s), 3.40 (1H, m), 3.28 (1H,m), 3.20 (3H, s), 1.06 (3H, d).

The intermediates for this compound were prepared as follows:

i) 2-Fluoro-3-methoxybenzoic acid

Pentamethylenediethylenetetramine (31.2 ml) was added to a solution of2-fluoroanisole (15.0 g) in TB (450 ml). The reaction mixture was cooledto −78° C. and n-butyllithium (59.6 ml, 2.5M solution in hexanes) wasadded dropwise. Stirring was maintained for 2 h before the solution wasadded in a dropwise fashion to a flask containing solid carbon dioxidepellets. Upon complete addition (30 min) the mixture was allowed to warmto room temperature before removal of the volatiles in vacuo. Theresidue was dissolved in 10% sodium hydroxide solution (300 ml) andextracted with Et₂O (3×). The aqueous was acidified to pH 1 withconcentrated hydrochloric acid before extracting with DCM. The organicswere washed with H₂O, dried (MgSO₄) and concentrated in vacuo to affordthe subtitle compound as a yellow solid. Yield: 7.1 g.

¹H NMR δ_((CDCl) ₃) 7.50 (1H, m), 7.12 (2H, m), 3.91 (3H, s).

ii) (2-Fluoro-3-methoxyphenyl)methanol

Lithium aluminium hydride (83.5 ml, 1M solution in THF) was addeddropwise to a suspension of the subtitle product of step i) (7.1 g) inEt₂O (180 ml) at a rate that maintained gentle reflux. Upon completeaddition the reaction was stirred for 1.5 h. 15% sodium hydroxidesolution was added dropwise until no effervescence was observed. Theresulting white precipitate was filtered and the filtrate diluted withH₂O (100 ml). The organics were removed in vacuo and the residueextracted with Et₂O (100 ml). The organics were washed with 2M sodiumhydroxide solution (150 ml), H₂O (150 ml), brine (150 ml), dried (MgSO₄)and concentrated in vacuo to afford the subtitle compound as a whitecrystalline solid. Yield: 5.5 g.

¹H NMR δ_((CDCl3)) 7.00 (3H, m), 4.77 (2H, d), 3.89 (3H, s), 1.77 (1H,t).

iii) 1-(Bromomethyl)-2-fluoro-3-methoxybenzene

Triphenylphosphine (11.1 g) was added to a solution of the subtitleproduct of step ii) (5.0 g) in DCM (200 ml) followed by the portionwiseaddition of carbon tetrabromide (14.0 g). The reaction was stirred for 4h before the addition of further triphenylphosphine (2.0 g) and carbontetrabromide (2.0 g) and stirring maintained for 1 h. The mixture wasconcentrated to 30 ml volume and diluted in Et₂O (300 ml). The solidprecipitate was filtered and washed with Et₂O (3×) and the filtrateconcentrated in vacuo. The residue was purified by column chromatography(10% Et₂O/iso-hexane) to afford the subtitle compound as a clear oil.Yield: 5.2 g.

¹H NMR δ_((CDCl3)) 7.05 (1H, m), 6.93 (2H, m), 4.52 (2H, s), 3.89 (3H,s).

iv) 2-[(2-Fluoro-3-methoxybenzyl)thio]pyrimidine-4,6-diol

The subtitle compound was prepared as a white solid by the method ofExample 39 step i) using 1-(bromomethyl)-2-fluoro-3-methoxybenzene (4.5g), 2-mercaptopyrimidine-4,6-diol (2.96 g) and potassium hydroxide (1.15g). Yield: 5.0 g.

¹H NMR δ_((DMSO)) 7.10 (3H, m), 5.21 (1H, bs), 4.38 (2H, s), 3.83 (3H,s).

v) 4,6-Dichloro-2-[(2-fluoro-3-methoxybenzyl)thio]pyrimidine

The subtitle compound was prepared as a white solid by the method ofExample 39 step ii) using the subtitle product of step iv) (4.91 g),phosphorus oxychloride (42.6 ml) and N,N-dimethylaniline (4.9 ml).Yield: 4.1 g.

¹H NMR δ_((DMSO)) 7.74 (1H, s), 7.09 (3H, m), 4.43 (2H, s), 3.83 (3H,s).

vi)N-{6-Chloro-2-[(2-fluoro-3-methoxybenzyl)thio]pyrimidin-4-yl}-N-{[2-(trimethylsilyl)ethoxy]methyl}methanesulfonamide

The subtitle compound was prepared as a colourless oil by the method ofExample 39 step iii) using the subtitle product of step v) (2.0 g),methanesulfonamide (0.60 g), 60% sodium hydride (0.50 g) and2-(trimethylsilyl)ethoxymethyl chloride (1.11 ml). Yield: 2.42 g.

MS APCI(+ve) 509 [M+H]⁺

vii)N-{6-Chloro-2-[(2-fluoro-3-methoxybenzyl)thio]pyrimidin-4-yl}-N-{[2-(trimethylsilyl)ethoxy]methyl}methanesulfonamide

A solution of the subtitle product of step vi) (0.3 g) in (R)-alaninol(1.5 ml) was stirred at 90° C. for 2.5 h. The reaction mixture wasdiluted in EtOAc (50 ml) and washed with water, brine, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by column chromatography(50% EtOAc/iso-hexane) to afford the subtitle compound as a gum. Yield:0.24 g.

MS APCI(+ve) 547 [M+H]⁺

EXAMPLE 121N-(2-[(2-Fluoro-3-methoxybenzyl)thio]-6-{[(1R)-1-(hydroxymethyl)propyl]amino}-pyrimidin-4-yl)methanesulfonamide

The title compound was prepared as a white foam by the method of Example40 using the subtitle product of step i) (0.24 g) and trifluoroaceticacid (10 ml). Yield: 0.11 g.

MS APCI(+ve) 431 [M+H]⁺

¹H NMR δ_((DMSO)) 7.10 (1H, bs), 7.06 (3H, m), 5.80 (1H, bs), 4.64 (1H,bs), 4.30 (2H, t), 3.85 (1H, bs), 3.82 (3H, s), 3.39 (1H, bm), 3.20 (3H,bs), 1.61 (1H, p), 1.36 (1H, p), 0.83 (3H, t).

The intermediates for this compound were prepared as follows:

i)N-(2-[(2-Fluoro-3-methoxy-benzyl)thio]-{6-{[(1R)-1-(hydroxymethyl)propyl]amino}-pyrimidin-4-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}methanesulfonamide

A solution of the subtitle compound of Example 120 step vi) (0.3 g) in(2R)-2-aminobutan-1-ol (1.5 ml) was stirred at 90° C. for 2.5 h. Thereaction mixture was diluted in EtOAc (50 ml) and washed with H₂O andbrine, dried (MgSO₄) and concentrated in vacuo. The residue was purifiedby column chromatography (50% EtOAc/iso-hexane) to afford the subtitlecompound as a gum. Yield: 0.26 g.

MS APCI(+ve) 561 [M+H]⁺

EXAMPLE 122N-{6-{[(1R)-2-Hydroxy-1-methylethyl]amino}-2-[(3-methoxy-2-methylbenzyl)thio]-pyrimidin-4-yl}-1,2-dimethyl-1H-imidazole-4-sulfonamide

A solution of the subtitle compound of step i) (0.4 g) and (R)-alaninol(0.11 ml) in NMP (11.0 ml) was stirred at 90° C. for 2 h. Upon coolingthe reaction mixture was diluted with acetonitrile (4 ml) and 2Mhydrochloric acid (1 ml) and stirring maintained for 10 min. The solventwas partially evaporated under reduced pressure and the reaction mixturediluted in EtOAc (50 ml) and washed with H₂O (5 ml), dried (MgSO₄) andconcentrated in vacuo to afford a yellow oil. The residue was purifiedby reverse phase HPLC (gradient 90% to 5% 0.02M ammoniumhydroxide/acetonitrile) to yield the title compound as a white solid.Yield: 12 mg.

MS APCI(+ve) 497 [M+H]⁺

¹H NMR δ_((DMSO)) 7.70 (1H, bs), 7.03 (4H, m), 5.88 (1H, bs), 4.69 (2H,bs), 3.90 (1H, bs), 3.54 (3H, s), 3.37 (1H, m), 3.28 (3H, s), 3.25 (1H,m), 2.26 (3H, s), 1.03 (3H, d).

The intermediates for this compound were prepared as follows:

i)N-{6-Chloro-2-[(3-methoxy-2-methylbenzyl)thio]pyrimidin-4-yl}-1,2-dimethyl-N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-4-sulfonamide

The subtitle compound was prepared as a colourless oil by the method ofExample 39 step iii) using the subtitle product of Example 120 step v)(2.3 g), 1,2-dimethyl-1H-imidazole-4-sulfonamide (0.60 g), 60% sodiumhydride (0.87 g) and 2-(trimethylsilyl)ethoxymethyl chloride (1.5 ml).Yield: 2.2 g.

MS APCI(+ve) 646 [M+H]⁺

EXAMPLE 123N-{6-[(2-Hydroxy-1,1-dimethylethyl)amino]-2-[(3-methoxy-2-methylbenzyl)thio]pyrimidin-4-yl}-1,2-dimethyl-1H-imidazole-4-sulfonamide

The title compound was prepared as a white solid by the method ofExample 122 using the subtitle product of Example 122 step i) (0.40 g)and 2-amino-2-methylpropan-1-ol (0.20 ml) then 2M hydrochloric acid (1.0ml). Yield: 13 mg.

MS APCI(+ve) 511 [M+H]⁺

¹H NMR δ_((DMSO)) 7.28 (1H, bs), 7.04 (3H, m), 5.23 (1H, bs), 5.72 (1H,s), 4.23 (2H, s), 3.82 (3H, s), 3.52 (3H, s), 3.35 (2H, bs), 2.25 (3H,s), 1.18 (6H, s).

EXAMPLE 124N-{6-{[(1R)-1-(Hydroxymethyl)propyl]amino})-2-[(3-methoxy-2-methylbenzyl)thio]pyrimidin-4-yl}-1,2-dimethyl-1H-imidazole-4-sulfonamide

The title compound was prepared as a white solid by the method ofExample 122 using the subtitle product of Example 122 step i) (0.40 g),and (R)-2-aminobutanol (0.19 ml) then 2M hydrochloric acid (1.0 ml).Yield: 46 mg.

MS APCI(+ve) 511 [M+H]⁺

¹H NMR δ_((DMSO)) 7.72 (1H, bs), 7.03 (1H, bs), 7.00 (3H, bs), 5.92 (1H,bs), 4.62 (1H, bs), 4.26 (2H, s), 3.82 (4H, bs+s), 3.54 (3H, s), 3.36(1H, m), 2.27 (3H, s), 1.57 (1H, m), 1.35 (1H, m), 0.81 (3H, t).

EXAMPLE 125N-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-1,1,1-trifuoromethanesulfonamide

Triflic anhydride (0.38 ml) was added dropwise to a solution of thesubtitle product of Example 3 step ii) (0.4 g) andN,N-diisopropylethylamine (1.7 ml) in DCM at −10° C. After 15 minsaturated sodium bicarbonate (10 ml) was added and the organicsrecovered through extraction with DCM (2×10 ml). The organics werecombined, washed with H₂O, brine, dried (MgSO₄) and concentrated invacuo. The residue was dissolved in THF (10 ml) and treated withtetrabutylammonium fluoride (5 ml, 1M in THF) for 15 mins beforeacidifying to pH 1 with 1M hydrochloric acid. EtOAc (10 ml) was addedbefore the organics were washed with brine, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by column chromatography(2% methanol/DCM) to afford a gum which was freeze dried from dioxane(20 ml) to yield title compound as a foam. Yield: 0.37 g.

MS APCI(+ve) 422 [M+H]⁺

¹H NMR δ_((DMSO)) 13.30 (1H, s), 8.44 (1H, d), 7.42 (2H, d), 7.37-7.24(3H, m), 6.20 (1H, s), 4.48-4.41 (2H, m), 4.28-4.16 (1H, m), 3.46-3.28(2H, m), 1.09 (3H, d).

EXAMPLE 126N-(2-(Benzylthio)-5-chloro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)methanesulfonamide

The title compound of Example 3 (0.4 g) was dissolved in DCM (20 ml) andtreated with N-chlorosuccinimide (0.14 g) for 2 h. The volatiles wereremoved in vacuo and the residue purified by reverse phase HPLC((gradient 95% to 20% 0.02M ammonium hydroxide/acetonitrile) to yieldthe title compound as a white solid. Yield: 0.25 g.

MS APCI(−ve) 402 [M−H]⁻

¹H NMR δ_((DMSO)) 10.33 (1H, s), 7.41 (2H, d), 7.35-7.20 (3H, m), 6.76(1H, d), 4.79 (1H, t), 4.39-4.29 (2H, m),4.28-4.16 (1H, m), 3.50-3.31(2H, m), 1.12 (3H, d).

EXAMPLE 127N-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-2-chlorobenzenesulfonamide

2-Chlorophenylmethanesulfonyl chloride (0.17 g) was added to a solutionof the subtitle product of Example 3 step ii) (66 mg) in pyridine (2 ml)and N,N-dimethylaminopyridine (24 mg). The reaction mixture was stirredfor 18 h. The volatiles were removed under reduced pressure and theresidue diluted in THF (5 ml) and treated with 2M hydrochloric acid (5ml) for 5 min. The solvent was evaporated and the residue partitionedbetween DCM and treated with saturated sodium bicarbonate to pH neutral.The organic layer was washed with H₂O and brine. The organics were dried(MgSO₄) and concentrated to yield a solid. This material was purified bycolumn chromatography (20% EtOAc/DCM) to yield the title compound as anorange solid. Yield: 19 mg.

MS APCI(+ve) 464 [M+H]⁺

¹H NMR δ_((DMSO)) 10.88 (1H, s), 8.07 (1H, d), 7.66 (2H, m), 7.56 (1H,m), 7.27 (5H, m), 6.45 (1H, bd), 6.09 (1H, s), 5.91 (1H, s), 4.24 (2H,q), 3.85 (1H, bt), 3.30 (2H, m), 1.02 (3H, d).

EXAMPLE 128N-(2-[(3,4-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)methanesulfonamide

The title compound was prepared by the method of Example 27 using thesubtitle product of step iii) (0.3 g) and methanesulfonyl chloride (0.16ml). Yield: 77 mg.

MS APCI(+ve) 405 [M+H]⁺

¹H NMR δ_((DMSO)) 7.51 (1H, m), 7.33 (2H, m), 5.78 (1H, s), 4.70 (1H,bs), 4.30 (2H, q), 3.95 (1H, bs), 3.33 (2H, m), 3.20 (3H, s), 1.05 (3H,d).

The intermediates for the above compound were prepared as follows:

i) 6-Amino-2-[(3,4-difluorobenzyl)thio]pyrimidin-4-ol

The subtitle compound was prepared according to the procedure of Example1 step i) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate(2.0 g) with 3,4-difluorobenzyl bromide (2.66 g) to afford the subtitlecompound as a white solid. Yield: 3.35 g.

¹H NMR δ_((DMSO)) 7.54 (1H, m), 7.32 (2H, m), 6.58 (2H, bs), 4.96 (1H,bs), 4.29 (2H, s).

ii) 6-Chloro-2-[(3,4-difluorobenzyl)thio]pyrimidin-4-amine

The subtitle compound was prepared from the product of step i) (3.35 g)according to the procedure of Example 1 step ii) to afford the subtitleproduct as a green foam which was used directly in the subsequent step.

MS: APCI(+ve) 368 [M+H]⁺

iii)N-((1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-[(3,4-difluorobenzyl)-thio]pyrimidine-4,6-diamine

N,N-Diisopropylethylamine (4.9 ml) was added to a solution of(R)-alaninol (5.0 ml) and the subtitle product of step ii) and stirredat 120° C. for 7 days before partitioning between H₂O and DCM. Theorganics were washed with H₂O, brine, dried (MgSO₄) and concentrated invacuo to afford a residue which was purified by column chromatography(8:1 EtOAc/iso-hexane). The residue was treated with imidazole (0.29 g)and a solution of tert-butyldimethylsilyl chloride (0.63 g) in DMF (1.5ml) and stirring maintained for 18 h. The reaction mixture waspartitioned between EtOAc and H₂O and the organics recovered, dried(MgSO₄) and concentrated in vacuo. The residue was purified by columnchromatography (6:4 Et₂O/iso-hexane) to afford the subtitle compound asan orange gum. Yield: 0.61 g.

MS: APCI(+ve) 441 [M+H]⁺

EXAMPLE 129N-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide

The title compound was prepared by the method of Example 127 using thesubtitle product of Example 3 step ii) (0.2 g) and2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride(0.49 g). Yield: 84 mg.

MS APCI(+ve) 486 [M+H]⁺

¹H NMR δ_((DMSO/D2O)) 7.59 (1H, d) 7.55 (1H, s), 7.27 (6H, m), 5.65 (1H,s), 4.17 (2H, t), 4.01 (2H, s), 3.81 (1H, bs), 3.37 (1H, m), 3.24 (1H,m), 3.09 (2H, t), 2.84 (2H, t), 1.03 (3H, d).

EXAMPLE 1305-{[(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)amino]sulfonyl}-2-furoicacid

Hydrogen chloride (2 ml, 4M in dioxan) was added to the subtitle productof step ii) (30 mg) and stirred for 2 h. The volatiles were removed invacuo and the residue purified by reverse phase HPLC (gradient 95% to50% 0.02M ammonium hydroxide/acetonitrile) to yield the title compoundas a white solid. Yield: 20 mg.

MS APCI(+ve) 436 [M+H]⁺

¹H NM (DMSO) 7.40 (2H, d), 7.30 (3H, m), 6.97 (1H, d), 6.91 (1H, d),5.85 (1H, s), 4.34 (2H, q), 4.02 (1H, bs), 3.39 (1H, m), 3.30 (1H, m),1.07 (3H, d).

The intermediates for this compound were prepared as follows:

i) Methyl5-[({2-(benzylthio)-6-[((1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)amino]pyrimidin-4-yl}amino)sulfonyl]-2-furoate

Methyl 5-(chlorosulfonyl)-2-furoate (0.54 g) was added to the solutionof the subtitle product of Example 3 step ii) (0.5 g) in pyridine (15ml) and N,N-dimethylaminopyridine (0.15 g). The reaction mixture wasstirred for 18 h. A further aliquot of the sulfonyl chloride (0.27 g)was added and stirring maintained for a further 18 h. The solvent wasevaporated and the residue purified by column chromatography (25%EtOAc/iso-hexane) to yield the subtitle compound as a yellow glass.Yield: 0.24 g.

¹H NMR δ_((DMSO)) 7.38 (7H, m), 7.09 (1H, bs), 5.95 (1H, s), 4.42 (2H,s), 4.26 (1H, bs), 3.87 (3H, s), 3.54 (2H, bm), 1.12 (3H, d), 0.85 (9H,s), 0.01 (6H, m).

ii)5-[({2-(Benzylthio)-6-[((1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)amino]pyrimidin-4-yl}amino)sulfonyl]-2-furoicacid

Lithium hydroxide (33 mg) was added to a solution of the subtitleproduct of step i) (0.23 g) in THF/H₂O (1 ml/1 ml) and stirringmaintained for 1 h. The THF was removed in vacuo and the residueneutralised with AcOH before extracting with EtOAc. The organics werethen washed with H₂O, dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by reverse phase HPLC (gradient 95% to 20% 0.02Mammonium hydroxide/acetonitrile) to yield the title compound as anoff-white solid. Yield: 0.14 g.

¹H NMR δ_((DMSO)) 7.13 (6H, m), 6.84 (2H, d), 5.72 (1H, s), 4.26 (2H,s), 3.93 (1H, bs), 3.58 (1H, m), 3.34 (1H, m), 1.07 (3H, d), 0.84 (9H,s), 0.00 (6H, s).

EXAMPLE 131N-(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-5-(piperazin-1-ylcarbonyl)furan-2-sulfonamide

Hydrogen chloride (2 ml, 4M in dioxan) was added to the subtitle productof step i) (0.12 g) and stirred for 2 h. The volatiles were removed in:vacuo and the residue purified by reverse phase HPLC (gradient 95% to50% 0.02M ammonium hydroxide/acetonitrile) to yield the title compoundas a white solid. Yield: 68 mg. MS APCI(+ve) 533 [M+H]⁺

¹H NMR δ_((DMSO)) 7.35 (2H, d), 7.24 (3H, m), 7.02 (1H, d), 6.86 (1H,d), 5.68 (1H, s), 4.21 (2H, t), 3.84 (1H, bs), 3.73 (4H, bs), 3.38 (1H,m), 3.25 (1H, m), 3.01 (4H, bs), 1.05 (3H, d).

The intermediates for this compound were prepared as follows:

i) tert-Butyl4[({2-(benzylthio)-6-[((1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-ethyl)amino]-pyrimidin-4-yl}amino)sulfonyl]piperazine-1-carboxylate

tert-Butylpiperazine-1-carboxylate (45 mg), N-hydroxybenzotriazole (33mg), and then dicyclohexylcarbodiimide (50 mg) were added to a solutionof the subtitle product of Example 130 step ii) (0.14 g) in DCM (5 ml).After 1 h the reaction ws filtered and washed well with DCM. Thecombined filtrates were washed with brine, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by column chromatography(40% EtOAc/iso-hexane) to yield the subtitle compound as a white solid.Yield: 0.17 g.

MS APCI(+ve) 747 [M+H]⁺

EXAMPLE 1325-{[(2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)amino]sulfonyl}-N,N-dimethyl-2-furamide

2M Hydrochloric acid (10 ml) was added to a solution of the subtitleproduct of step i) (0.20 g) in THF (10 ml) and stirred for 3 h. Thevolatiles were removed in vacuo and the residue was extracted with DCM.The organics were washed with brine, dried (MgSO₄) and concentrated invacuo. The residue was purified by reverse phase HPLC (gradient 95% to50% 0.02M ammonium hydroxide/acetonitrile) to yield the title compoundas a white solid. Yield: 31 mg.

MS APCI(−ve) 490 [M−H]⁻

¹H NMR δ_((DMSO)) 7.39 (2H, d), 7.28 (3H, m), 7.05 (2H, bs), 5.93 (1H,vbs), 4.78 (1H, bs), 4.35 (2H, bs), 4.13 (1H, vbs), 3.40 (2H, m), 3.09(3H, bs), 2.95 (3H, bs), 1.07 (3H, d).

The intermediates for this compound were prepared as follows:

i)5-[({2-(Benzylthio)-6-[((1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)amino]-pyrimidin-4-yl}amino)sulfonyl]-N,N-dimethyl-2-furamide

A solution of the subtitle product of Example 130 step i) (0.37 g) in40% aqueous dimethylamine (4.2 ml) was stirred for 18 h. The volatileswere removed in vacuo and the residue extracted with EtOAc. The organicswere washed with brine, dried (MgSO₄) and concentrated in vacuo. Theresidue purified by column chromatography (50% EtOAc iso-hexane) toyield the subtitle compound as a yellow gum. Yield: 0.14 g.

MS APCI(+ve) 606 [M+H]⁺

EXAMPLE 133N-(2-[(3-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-cis-3,5-dimethylpiperazine-1-sulfonamide

The title compound was prepared as a white solid by the method ofExample 39 using the subtitle product of step ii) (0.37 g), and(R)-alaninol (1 ml). Yield: 6 mg.

MS APCI(+ve) 519 [M+H]⁺

¹H NMR δ_((DMSO)) 7.59 (1H, t), 7.47 (1H, p), 7.15 (1H, s), 5.80 (1H,s), 4.67 (1H, t), 4.35 (2H, s), 3.90 (1H, bs), 3.57 (2H, s), 3.38 (4H,m), 2.24 (2H, t), 1.04 (3H, d), 0.94 (6H, d).

The intermediates for this compound were prepared as follows:

i) cis-3,5-dimethylpiperazine-1-sulfonamide

A solution of cis-2,6-dimethylpiperazine (5.0 g) and sulfamide (10.0 g)in 1,4-dioxane (100 ml) was stirred for 72 h at 110° C. The volatileswere removed in vacuo and the residue suspended in EtOAc. The filtratewas evaporated to a yellow solid (4.3 g). 1 g of this material wasdissolved in methanol and applied to an SCX cartridge (10 g). Thecartridge was washed with 50% aqueous methanol (200 ml) before thesubtitle product was eluted with 5% ammonium hydroxide solution/methanol(200 ml). The solvent was removed under reduced pressure to yield thesubtitle compound as a yellow solid. Yield: 0.46 g.

MS APCI(+ve) 194 [M+H]⁺

ii)N-(6-chloro-2-[(3-chloro-2-fluorobenzyl)thio]-pyrimidin-4-yl)-cis-3,5-dimethyl-piperazine-1-sulfonamide

60% Sodium hydride (0.19 g) was added to a stirred solution of thesubtitle product of step i) (0.45 g) in DMF (4.2 ml) at 0° C. Thecooling bath was removed for 15 min before recooling to 0° C. andaddition of a solution of the subtitle product of Example 31 step iii)(0.76 g) in DMF (2 ml). After stirring at room temperature for 3 h themixture was acidified with 2M hydrochloric acid to pH 4 and thevolatiles were removed in vacuo. The residue was dissolved in methanoland applied to an SCX cartridge (10 g). The cartridge was washed withmethanol (200 ml) before the subtitle product was eluted with 10%triethylamine/methanol (300 ml). The solvent was removed under reducedpressure and the residue triturated from Et₂O to yield the subtitlecompound as a yellow solid. Yield: 0.37 g.

MS APCI(+ve) 480/482/484 [M+H]⁺

EXAMPLE 134N-(2-[(3-Chloro-2-fluorobenzyl)thio]-6{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-4-ethylpiperazine-1-sulfonamide

A solution of the subtitle product of step ii) (1.92 g) in (R)-alaninol(5 ml) was heated at 80° C. for 72 h. The reaction mixture was thendiluted in methanol and purified by reverse phase HPLC (gradient 95% to60% 0.02M ammonium hydroxide/acetonitrile) to yield the title compoundas a yellow glass. Yield: 90 mg.

MS APCI(+ve) 519 [M+H]⁺

¹H NMR δ_((DMSO)) 7.59 (1H, t), 7.47 (1H, t), 7.16 (2H, bt), 5.86 (1H,s), 4.69 (1H, bm), 4.36 (2H, t), 3.91 (1H, vbs), 3.38 (2H, m), 3.12 (4H,bs), 2.28 (6H, m), 1.05 (3H, d), 0.96 (3H, t).

The intermediates for this compound were prepared as follows:

i) 4-Ethylpiperazine-1-sulfonamide

A solution of N-ethylpiperazine (5.0 g) and sulfamide (10.0 g) in1,4-dioxane (100 ml) was stirred for 72 h at 110° C. The volatiles wereremoved in vacuo and 5 g of the residue was dissolved in methanol andapplied to an SCX cartridge (70 g). The cartridge was washed with 50%aqueous methanol (200 ml) before the subtitle product was eluted with10% triethylamine/methanol (100 ml) The solvent was removed underreduced pressure to yield the subtitle compound as a pale beige solid.Yield: 3.0 g.

MS APCI(−ve) 192 [M−H]⁻

ii)N-[6-Chloro-2-[(3-chloro-2-fluorobenzyl)thio]pyrimidin-4-yl]-4-ethylpiperazine-1-sulfonamide

The subtitle compound was prepared as an orange gum by the method ofExample 133 step ii) using the subtitle product of step i) (3.0 g), 60%sodium hydride (1.24 g) and the subtitle product of Example 31 step iii)(5.0 g). Yield: 0.73 g.

MS APCI(+ve) 480 [M+H]⁺

EXAMPLE 135N-{2-[(3-Chloro-2-fluorobenzyl)thio]-6-[(2-hydroxy-1,1-dimethylethyl)amino]-pyrimidin-4-yl}-cis-3,5-dimethylpiperazine-1-sulfonamide

A solution of the subtitle product of step i) (0.26 g) in2-amino-2-methylpropanol (1 ml) was heated at 90° C. for 3.5 h and then55° C. for 72 h. The reaction mixture was then diluted in EtOAc andwashed with H₂O, dried (Na₂SO₄) and concentrated in vacuo. The residuewas diluted in trifluoroacetic acid (2 ml) and stirred for 15 min beforeremoval of the volatiles in vacuo and azeotroping the residue withtoluene (2×). The crude material and purified by reverse phase BPLC(gradient 95% to 50% 0.02M ammonium hydroxide/acetonitrile) to yield thetitle compound as a solid. Yield: 48 mg.

MS APCI(+ve) 533 [M+H]⁺

¹H NMR δ_((DMSO)) 7.58 (1H, t), 7.47 (1H, t), 7.17 (1H, t), 5.88 (1H,s), 4.36 (2H, s), 3.46 (4H, m), 2.73 (2H, bs), 2.30 (2H, t), 1.21 (6H,s), 0.97 (6H, d).

The intermediates for this compound were prepared as follows:

i)N-{6-Chloro-2-[(3-chloro-2-fluorobenzyl)thio]pyrimidin-4-yl}-cis-3,5-dimethyl-N-{[2-(trimethylsilyl)ethoxy]methyl}piperazine-1-sulfonamide

The subtitle compound was prepared as a yellow gum by the method ofExample 39 step iii) using the subtitle product of Example 133 step i)(2.6 g), the subtitle product of Example 31 step iii) (4.35 g), 60%sodium hydride (0.99 g) and 2-(trimethylsilyl)ethoxymethyl chloride(2.38 ml). Yield: 3.4 g.

MS APCI(+ve) 610 [M+H]⁺

EXAMPLE 136N-{6-{[(1R)-2-Hydroxy-1-methylethyl]amino}-2-(R,S)-[(1-phenylethyl)thio]pyrimidin-4-yl}methanesulfonamide

Methanesulfonyl chloride (0.16 ml) was added to a stirred solution ofthe subtitle product of step ii) (0.29 g) and N,N-diisopropylethylamine(0.36 ml) in DCM (5 ml). After stirring for 18 h the volatiles wereremoved under reduced pressure and the residue diluted in THF (8 ml) andtreated with 1M sodium hydroxide solution (4.2 ml). After 6 h 2Mhydrochloric acid was added to pH 1 and stirring maintained for 3 days.The reaction mixture was then neutralised with saturated sodiumbicarbonate solution and the product extracted with DCM. The organicswere washed with H₂O, dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified by reverse phase HPLC (gradient 95% to 25% 0.02Mammonium hydroxide/acetonitrile) to yield the title compound as a whitesolid. Yield: 90 mg.

MS APCI(+ve) 383 [M+H]+

¹H NMR δ_((DMSO)) 7.45 (2H, d), 7.33 (2H, t), 7.24 (1H, m), 5.77 (1H,bs), 4.93 (1H, q), 4.71 (1H, bs), 3.41 (1H, m), 3.30 (1H, m), 3.23 (3H,bs), 1.67 (3H, dd), 1.07 (3H, dd).

The intermediates for the title compound were prepared as follows:

i) 6-Amino-2-[(1-phenylethyl)thio]pyrimidin-4-ol

The subtitle compound was prepared according to the procedure of Example1 step i) treating 4-amino-6-hydroxy-2-mercaptopyrrinidine monohydrate(5.0 g) with □-methylbenzyl bromide (5.74 g) to afford the subtitlecompound which was used directly in the subsequent step.

MS APCI(+ve) 352 [M+H]⁺

ii)N-((1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-(R,S)-[(1-phenylethyl)thio]-pyrimidine-4,6-diamine

The subtitle compound was prepared from the product of step i) accordingto the procedure of Example 1 step ii) to afford the subtitle product asa green foam which was then diluted in (R)-alaninol (12.2 ml),N,N-diisopropylethylamine (11.8 ml) and NMP (16 ml) and stirred at 130°C. for 3 days before partitioning between H₂O and DCM. The organics werewashed with H₂O, dried (MgSO₄) and concentrated in vacuo to afford aresidue which was purified by column chromatography (8:2EtOAc/iso-hexane). The residue was treated with imidazole (2.7 g) and asolution of tert-butyldimethylsilyl chloride (5.95 g) in DMF (30 ml) andstirring maintained for 18 h. The reaction mixture was partitionedbetween EtOAc and H₂O and the organics recovered, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by column chromatography(6:4 Et₂O/iso-hexane) to afford the subtitle compound as a gum. Yield:1.3 g.

MS: APCI(+ve) 419 [M+H]⁺

EXAMPLE 137N-{6-{[(1R)-2-hydroxy-1-methylethyl]amino}-2-[(2,3,4-trifluorobenzyl)thio]-pyrimidin-4-yl}methanesulfonamide

The title product was prepared from a solution of the product of Example43 step iv) (4 ml) and quenching with 2,3,4-trifluorobenzyl bromide (0.5g) using the method descibed for Example 43 to give the title compoundas a white foam. Yield: 32 mg.

MS APCI(+ve) 423 [M+H]⁺

EXAMPLE 138N-[2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-6-[(R)-(2-hydroxy-1-methylethyl)amino]-4-pyrimidinyl]-1-methyl-1H-imidazole-4-sulfonamide

The title compound was prepared as a white solid by the method ofExample 37 from the product of Example 27 step iii) (1.4 g) using1-methyl-1H-imidazole-4-sulfonyl chloride (1.0 g). Purification was bycolumn chromatography (DCM/methanol/AcOH 190:10:1). Yield: 1.0 g.

MS APCI(+ve) 488 [M+H]⁺

¹H NMR δ_((DMSO)) 7.85 (1H, bs), 7.75 (1H, s), 7.50 (2H, m), 7.18 (1H,m), 5.91(1H, m), 4.36 (2H, s), 3.60 (3H, s), 3.30 (2H, m), 1.10 (3H, d).

1. A compound of formula (1) or a pharmaceutically acceptable saltthereof:

wherein R¹ is a group selected from C₃₋₇carbocyclyl, C₁₋₈alkyl,C₂₋₆alkenyl and C₂₋₆alkynyl; wherein the group is optionally substitutedby 1, 2 or 3 substituents independently selected from fluoro, nitrile,—OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶,—NR⁸SO₂R⁹, phenyl or heteroaryl; wherein phenyl and heteroaryl areoptionally substituted by 1, 2 or 3 substituents independently selectedfrom halo, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹,—SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁₋₆alkyl and trifluoromethyl;wherein R² is C₃₋₇carbocyclyl, optionally substituted by 1, 2 or 3substituents independently selected from: (a) fluoro, —OR⁴,—NR⁵R⁶—CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹;(b) a 3-8 membered ring optionally containing 1, 2 or 3 atoms selectedfrom O, S, —NR⁸ and whereby the ring is optionally substituted byC₁₋₃alkyl or fluoro; or (c) phenyl or heteroaryl, each of which isoptionally substituted by 1, 2 or 3 substituents independently selectedfrom halo, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —NR⁸COR⁹, —SO₂NR⁵R⁶,—NR⁸SO₂R⁹, C₁₋₆alkyl and trifluoromethyl; or R² is a group selected fromC₁₋₈alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl wherein the group is substitutedby 1, 2 or 3 substituents independently selected from hydroxy, amino,C₁₋₆alkoxy, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino,N—(C₁₋₆alkyl)-N-(phenyl)amino, N—C₁₋₆alkylcarbamoyl,N,N-di(C₁₋₆alkyl)carbamoyl, N—(C₁₋₆alkyl)-N-phenyl)carbamoyl, carboxy,phenoxycarbonyl, —NR⁸COR⁹, —SO₂R¹⁰, —SO₂NR⁵R⁶ and —NR⁸SO₂R⁹; wherein R³is hydrogen or independently R²; R⁴ is hydrogen or a group selected fromC₁₋₆alkyl and phenyl, wherein the group is optionally substituted by 1or 2 substituents independently selected from halo, phenyl, —OR¹¹ and—NR¹²R¹³; R⁵ and R⁶ are independently hydrogen or a group selected fromC₁₋₆alkyl and phenyl wherein the group is optionally substituted by 1, 2or 3 substituents independently selected from halo, phenyl, —OR¹⁴,—NR¹⁵R¹⁶, —COOR¹⁴, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SO2R¹⁰, —SONR¹⁵R¹⁶ andNR¹⁵SO₂R¹⁶ or R⁵ and R⁶ together with the nitrogen atom to which theyare attached form a 4- to 7-membered saturated heterocyclic ring systemoptionally containing a further heteroatom selected from oxygen andnitrogen atoms, which ring is optionally substituted by 1, 2 or 3substituents independently selected from phenyl, —OR¹⁴, —COOR¹⁴,—NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —N¹⁵COR¹⁶, —SO2R¹⁰, —SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ orC₁₋₆alkyl (optionally substituted by 1 or 2 substituents independentlyselected from halo, —NR¹⁵R¹⁶ and —OR¹⁷ groups); R¹⁰ is hydrogen or agroup selected from C₁₋₆alkyl or phenyl, wherein the group is optionallysubstituted by 1, 2 or 3 substituents independently selected from halo,phenyl, —OR¹⁷ and —NR¹⁵R¹⁶; and each of R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴R¹⁵, R¹⁶, R¹⁷ is independently hydrogen, C₁₋₆alkyl or phenyl; X ishydrogen, halo, cyano, nitro, hydroxy, C₁₋₆alkoxy (optionallysubstituted by 1 or 2 substituents selected from halo, —OR¹¹ and—NR¹²R¹³), —NR⁵R⁶, —COOR⁷, —NR⁸COR⁹, thio, C₁₋₆alkylthio (optionallysubstituted by 1 or 2 substituents selected from halo, —OR¹⁷, —NR¹⁵R¹⁶),—SO₂R¹⁰ or a group selected from C₃₋₇carbocyclyl, C₁₋₈alkyl, C₂₋₆alkenylor C₂₋₆alkynyl, wherein the group is optionally substituted by 1, 2 or 3substituents independently selected from halo, —OR⁴, —NR⁵R₆, —CONR⁵R⁶,—COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶ and —NR⁸SO₂R⁹; R^(x) istrifluoromethyl, —NR⁵R⁶, phenyl, napthyl, monocyclic or bicyclicheteroaryl wherein a heteroring may be partially or fully saturated andone or more ring carbon atoms may form a carbonyl group, and whereineach phenyl or heteroaryl group is optionally substituted by 1, 2 or 3substituents independently selected from halo, cyano, nitro, —OR⁴,—NR⁵R⁶, —CONR⁵R⁶, —COR⁷, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶,—NR⁸SO₂R⁹, C₁₋₆alkyl or trifluoromethyl; or R^(x) is a group selectedfrom C₃₋₇carbocyclyl, C₁₋₈alkyl, C₂₋₆alkenyl and C₂₋₆alkynyl whereby thegroup is optionally substituted by 1, 2 or 3 substituents independentlyselected from halo, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COR⁷, —COOR⁷, —NR⁸COR⁹,—SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, phenyl or heteroaryl; and whereineach phenyl or heteroaryl group is optionally substituted by 1, 2 or 3substituents independently selected from halo, cyano, nitro, —OR⁴,—NR⁵R⁶, —CONR⁵R⁶, —COR⁷, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶,—NR⁸SO₂R⁹, C₁₋₆alkyl or trifluoromethyl; or R^(x) and X together form a4 to 8-membered sulfonamide ring optionally substituted by 1, 2 or 3substituents independently selected from halo, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶,—COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, phenyl orheteroaryl; wherein phenyl and heteroaryl are optionally substituted by1, 2 or 3 substituents independently selected from halo, cyano, nitro,—OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶,—NR⁸SO₂R⁹, C₁₋₆alkyl and trifluoromethyl.
 2. A compound or apharmaceutically acceptable salt thereof according to claim 1 wherein R²is C₁₋₈alkyl substituted by 1 or 2 hydroxy substituents.
 3. A compoundor a pharmaceutically acceptable salt thereof according to claim 1wherein R¹ is benzyl optionally substituted by 1, 2 or 3 sub stituentsindependently selected from fluoro, chloro, bromo, methoxy, methyl andtrifluoromethyl.
 4. A compound or a pharmaceutically acceptable saltthereof according to claim 1 wherein R³ hydrogen.
 5. A compound or apharmaceutically acceptable salt thereof according to claim 1 wherein Xis hydrogen.
 6. A compound or a pharmaceutically acceptable salt thereofaccording to claim 1 wherein R^(x) is methyl, 1-methylimidazolyl,1,2-dimethylimidazolyl, N,N-dimethylamino, azetidinyl, pyrolidinyl,morpholinyl and piperidinyl.
 7. A compound that isN-(2-[(3-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)methanesulfonamideor a pharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition comprising a compound or a pharmaceutically acceptable saltthereof according to claim 1; and a pharmaceutically-acceptable diluentor carrier.
 9. A pharmaceutical composition which comprises a compoundof formula (1) as defined in claim 1 or a pharmaceutically acceptablesalt thereof, in conjunction with another pharmaceutical agent.
 10. Apharmaceutical composition as claimed in claim 9 wherein the amount ofthe compound in the composition is effective for treating asthma,allergic rhinitis, COPD, inflammatory bowel disease, irritable bowelsyndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, orpsorlasis.
 11. A compound that isN-[2-[(3-Chloro-2-fluorobenzyl)thio]-6-[(2-hydroxy-1-methylethyl)amino]-4-pyrimidinyl]-4-morpholinesulfonamideor a pharmaceutically acceptable salt thereof.
 12. A compound that isN-[2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-6-[(2-hydroxy-1-methylethyl)amino]-4-pyrimidinyl]-1,2-dimethyl-1H-imidazole-4-sulfonamideor a pharmaceutically acceptable salt thereof.
 13. A compound that isN-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)piperidine-1-sulfonamideor a pharmaceutically acceptable salt thereof.
 14. A compound that isN-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)pyrrolidine-1-sulfonamideor a pharmaceutically acceptable salt thereof.
 15. A compound that isN-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)azetidine-1-sulfonamideor a pharmaceutically acceptable salt thereof.
 16. A compound that isN-{6-{[(1R)-2-Hydroxy-1-methylethyl]amino}-2-[(2,3,4-trifluorobenzyl)thio]-pyrimidin-4-yl}morpholine-4-sulfonamideor a pharmaceutically acceptable salt thereof.
 17. A compound that isN-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)morpholine-4-sulfonamideor a pharmaceutically acceptable salt thereof.
 18. A compound that isN-(2-[(3-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)azetidine-1-sulfonamideor a pharmaceutically acceptable salt thereof.
 19. A compound that isN-{6-{[(1R)-2-Hydroxy-1-methylethyl]amino}-2-[(2,3,4-trifluorobenzyl)thio]-pyrimidin-4-yl}azetidine-1-sulfonamide or apharmaceutically acceptable salt thereof.
 20. A compound that isN′-(2-[(3-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)-N,N-dimethylsulfamideor a pharmaceutically acceptable salt thereof.
 21. A compound that isN-[2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-6-[(R)-(2-hydroxy-1-methylethyl)amino]-4-pyrimidinyl]-1-methyl-1H-imidazole-4-sulfonamideor a pharmaceutically acceptable salt thereof.